**Evolution of Pauson-Khand Reaction: Strategic Applications in Total Syntheses of Architecturally Complex Natural Products (2016–2020)**

#### **Sijia Chen 1,**† **, Chongguo Jiang 1,**† **, Nan Zheng 1 , Zhen Yang 1,2,3, \* and Lili Shi 1, \***


Received: 23 September 2020; Accepted: 14 October 2020; Published: 16 October 2020

**Abstract:** Metal-mediated cyclizations are important transformations in a natural product total synthesis. The Pauson-Khand reaction, particularly powerful for establishing cyclopentenonecontaining structures, is distinguished as one of the most attractive annulation processes routinely employed in synthesis campaigns. This review covers Co, Rh, and Pd catalyzed Pauson-Khand reaction and summarizes its strategic applications in total syntheses of structurally complex natural products in the last five years. Additionally, the hetero-Pauson-Khand reaction in the synthesis of heterocycles will also be discussed. Focusing on the panorama of organic synthesis, this review highlights the strategically developed Pauson-Khand reaction in fulfilling total synthetic tasks and its synthetic attractiveness is aimed to be illustrated.

**Keywords:** metal-mediated reactions; Pauson-Khand reaction; cyclopentenones; natural products total syntheses

#### **1. Introduction**

The metal-mediated reaction plays an important role in constructing complex organic molecules [1–3]. The Pauson-Khand reaction (PKR), an effective set of annulation protocol defined in 1973 [4] for the construction of cyclopentenone-containing moieties, stands as a promising method to permit efficient cyclic frameworks. Its efficient and atom-economic elaboration to substituted cyclopentenones renders this process highly prized in the construction of architecturally complex natural products. Since reported more than 40 years ago [5–12], it has been developed with different metal catalytic systems, including Co [13–17], Rh [18–25], Ru [26–30], Ti [31–34], Ir [35–37], Ni [38], Mo [39,40], Fe [41]; and other metals could promote the PKR to build the heterocycle frameworks [42–44]. By identifying reactivity patterns for diverse PKR precursors in the prominent synthetic application, we aim to elevate this powerful reaction to a method of choice in the synthetic designation of complex biologically active entities.

#### *1.1. Classic PK Reaction Catalyzed by Co*

In 1973, I.U. Khand and P.L. Pauson found that the generation of enyne/Co2(CO)<sup>6</sup> complex with olefin as substrates could lead to the formation of cyclopentenone. Moving forward, P.L. Pauson **O C**

explored the substrate scope and limitations of this reaction [45]. Although the specific mechanism of PKR involving Co2(CO)<sup>8</sup> is still uncertain, the mechanism proposed by Magnus [46–48] and Schore [49] is widely recognized based on the reaction results of regioselectivity and stereoselectivity (Scheme 1). The rate-determining step is alkene coordination with the cobalt and then insertion into cobalt–carbon bond to form the cobaltacycle, accounting for the regiochemical and stereochemical outcomes. **2 2 R 2**

**R**

**R 1**

**R**

**Scheme 1.** Generally accepted mechanism of Pauson-Khand reaction with Co<sup>2</sup> (CO)8.

β The regioselectivity of PKR is influenced by both steric and electronic effects (Scheme 2). For electrically neutral substrates, the insertion of olefins to enyne/Co2(CO)<sup>6</sup> complex correlates with steric hindrance. The regioselectivity also has been demonstrated to be related to the electronegativity of alkynyl groups [50–52]. Under most circumstances, the electron-withdrawing group will be installed at the β position of cyclopentenone. It is noteworthy that the frontier molecular orbital (FMO) theory could be used to analyze the influence of olefins in PKR [53,54]. Moreover, subordinate interaction and the guiding group can affect the regioselectivity [55–57]. For allene-involved intramolecular PKR, a 5,7-bicyclic product is more inclined to be formed [58,59]. β

**Scheme 2.** Regioselectivity study of Pauson-Khand reaction.

As for the diastereoselectivity of intramolecular PKR, both substrate conformation (especially the allyl chiral center) and electronic effect are relevant parameters (Scheme 3). Krafft reported their reaction with electron-deficient alkynes, and the PKR product could be obtained with a high *dr* value when norbornene was involved as an olefin substrate [51,60].

**Scheme 3.** Diastereoselectivity study of intramolecular Pauson-Khand reaction.

Most of the Co-catalyzed PKR conditions require a relatively high temperature and long reaction time. To accelerate the reaction rate, Smit and Caple's group found that PKR could be promoted in a stepwise manner [61]. *N*-methylmorpholine oxide (NMO), acting as an additive, was reported to improve the reaction rate through oxidizing CO into CO<sup>2</sup> on the enyne/Co2(CO)<sup>6</sup> complex [62], forcing the cobalt to release a vacant orbital which can be coordinated with olefins [63]. Recently, the Dionicio Martinez-Solorio group demonstrated the value of 4-FBnSMe as a new, efficient, and recoverable/reusable thioether promoter in PKR by modulating the Lewis basicity of thioether to influence the rate of alkene insertion [64].

To circumvent the use of stoichiometric catalysts, some Lewis bases were discovered to achieve the catalytic version of PKR, such as phosphine ligand [65], tetramethyl thiourea [66], phosphane sulfide [14], and primary amines [67]. In 2005, the Milet and Gimbert groups converted to the density functional theory (DFT) and calculated the energy change of the PKR process with Lewis base [68]. The results indicate that the enyne/Co2(CO)6-alkene insertion is a reversible process, but the Lewis base coordination could reduce the energy and therefore make the olefin insertion process irreversible.

#### *1.2. PK Reaction Catalyzed by Rh and Pd*

 ( The first example of [RhCl(CO)2]<sup>2</sup> catalyzed PKR was reported by Narasaka et al. in 1998 [18]. In their studies, the use of toluene as a reaction media reduced the loading of Rh catalysts and a good reaction reactivity was achieved with electron-deficient alkynes [69]. Moreover, under a low partial pressure of CO, it can effectively speed up the reaction and decrease the reaction temperature. Jeong et al. reported the first case of rhodium-catalyzed asymmetric PKR in the presence of 2,2′ -*bis*(di-*p*-tolylphosphino)-1,1′ -binaphthyl(BINAP) and AgOTf [21]. Consiglio's group used the molecular sieve to adsorb CO, greatly reducing the reaction temperature and accelerating the rate [70]. They accomplished the asymmetric PKR at 0 ◦C with a 99% *ee* value. In the course of Wender and his co-workers' studies on the rhodium(I)-catalyzed intra- and intermolecular dienyl [2 + 2 + 1] PKR, they observed that when a diene was used in place of an alkene the reaction rate was significantly accelerated [71,72].

As the Rh-catalyzed PKR has several advantages, it has attracted the attention of many research groups to report their work in this area. Typical PKR requires the utilization of highly toxic CO gas. An important breakthrough was made by the Morimoto and Shibata groups, respectively by introducing metal carbonyl compounds as a masked CO source through transition metal decarbonylation to in situ generate CO in PKR [73]. Moreover, Chung's group developed the use of a highly beneficial cinnamyl-alcohol as a CO source in the presence of the Rh catalyst to obtain corresponding hetero-Pauson-Khand (hPK) products in an inexpensive, safe, and environmentally friendly manner [74]. The catalytic dehydrogenation of cinnamyl alcohol could produce cinnamaldehyde, followed by Wilkinson decarbonylation and carbonylation constructed the desired cyclic product. Benzyl formate [75] has also been exploited as a non-gas CO surrogate. In 2019, they further

demonstrated the utilization of the formic acid as a CO source in the formation of various bicyclic cyclopentenones. In their protocol, formic acid was employed as a bridging molecule for the conversion of CO<sup>2</sup> to CO, which represented an indirect approach for the chemical valorization of CO<sup>2</sup> in the construction of valuable heterocycles [76] (Scheme 4).

**Scheme 4.** Non-gas CO surrogates in the Pauson-Khand reaction for heterocycle's formation.

The theoretical analysis of Rh-catalyzed PKR diastereoselectivity was demonstrated by Baik's group [25]. They revealed that two possible mechanistic scenarios and the optimum selectivity could be attributed to a five-coordinate organorhodium complex. The larger energy gap between the diastereomers and the Rh meta-cyclization trend to occur at the *cis*-position site dominated the diastereoselectivity. Based on the high efficiency, reliability and excellent diastereoselectivity of Rh-catalyzed PKR, its extraordinary impact on the synthetic campaign as a key step has been recognized [77].

π π Few metals could be applied in the catalytic PKR (Co, Ti, Rh, Ir, Ru) as most of them are air and moisture sensitive, and as such, it accounted for some limitations in synthetic applications. A series of thiourea and Pd-catalyzed reactions were developed by Yang's group [78–81] (Scheme 5). PdCl<sup>2</sup> coordinated to a thiourea ligand could catalyze an intramolecular PKR under mild conditions [81,82], and some interesting features were observed in this novel step. It could be catalyzed by PdCl<sup>2</sup> alone with a low yield, whereas using thiourea, especially tetramethyl thiourea (TMTU), as a reaction additive could greatly increase the yield; the Lewis acids addition such as LiCl can increase both the reaction rate and yield. Based on this observed phenomenon, further DFT calculation and mechanism investigation were carried out [83]. According to the coordination mode of the transition state, the TMTU ligand and substrate are lying both on the same side of the Pd catalyst thus the trans-diastereomer in substituted cases outperformed its diastereoisomer. It is speculated that changes in thiourea ligands may affect the diastereoselectivity of PKR through steric effect and π-π interaction, etc. π π

**Scheme 5.** Tetramethyl thiourea (TMTU) and Pd-catalyzed Pauson-Khand reaction.

#### *1.3. Hetero-Pauson-Khand Reaction*

The hetero-Pauson-Khand reaction has been harnessed as an effective tactic in the concise construction of functionalized polycyclic butenolides and α, β-unsaturated lactams (Scheme 6). In 1996, Crowe et al. reported the direct synthesis of bicyclic γ-butyrolactones via tandem reductive cyclization-carbonylation of tethered enals and enones [84,85]. In the same year, Buchwald et al. presented the heteroatom variant of the intramolecular PKR catalyzed by Cp2Ti(PMe3)2, in which the alkene could be replaced with a carbonyl for the diastereoselective synthesis of γ-butyrolactones or a fused butenolide, respectively [86,87]. Later on, chemists devoted themselves in the development of hetero-Pauson-Khand reaction, including Murai [28,88], Carretero [89], Saito [90], and Snapper [91]. However, the application of hPK in a natural product total synthetic work is relatively rare and therefore is underexplored in the synthetic version [92–96]. α β γ γ

**Scheme 6.** Hetero-Pauson-Khand reaction in natural products total syntheses.

#### *1.4. Summary*

Cobalt, rhodium, and palladium were involved in PK reactions represented in different advantageous patterns, among which the outstanding superiorities are as follows: a. Cobalt-catalyzed PKRs can overcome the high tension and construct an all-carbon quaternary chiral center [7,97–99]; b. rhodium-catalyzed PKRs normally exhibit excellent diastereoselectivity and are attractive in building a variety of ring structures; c. palladium-catalyzed PKRs could lead to the opposite stereoselectivity compared with others and are more operable due to the stability of Palladium species. Co/Rh-catalyzed PKRs are already widely applied in natural products total syntheses, in contrast, restriction existed in Pd-catalyzed PKRs and most of the work is still under methodological study.

The stereoselective formation of quaternary chiral centers is challenging in the construction of the cyclic system. PKR is an effective method for generating 5,5-bicyclic ring systems and has already been studied comprehensively. In 1984, Schore's group reported the first case of PKR to construct a 5,5,5-tricyclic skeleton containing an all-carbon quaternary chiral center [100]. Numerous research groups reported their studies and applications in natural products total syntheses. Joseph M. Fox et al. applied a thiourea-facilitated PKR in establishing the quaternary center and built a 5,5,3-tricyclic framework, and then completed the enantioselective total synthesis of (−)-pentalenene [101]. In the past few years, many chemists have made their efforts to broaden the application of the intramolecular PKR in natural products total syntheses, with some reviews already published [5–12]. In this mini-review, a perspective on the development of strategic Pauson-Khand reaction within natural products total syntheses portfolio over the past five years is presented by the categories of the constructed bicyclic ring systems (5,5/5,6/5,7- and macrocycles), with the aim to provide an updated overview of its tremendous power and versatility.

#### **2. Recent Pauson-Khand Reaction Applications in Natural Products Total Syntheses**

PKR proved to be a powerful strategy in natural products syntheses, particularly in those containing fused five-membered rings. The tethered length plays an important role in the efficiency and viability of all intramoleculars.

Pauson-Khand-like reactions [102], and the substrates with tethers that result in the formation of a five-membered ring are most effective in a great variety of intramolecular reactions [103]. Collections of 5,5/5,6/5,7-bicyclic ring systems or even macrocycles could be accessed depending on substrate identity as shown in this review.

#### *2.1. Construction of 5,5-Bicyclic Ring Systems*

Ryanodol is a bioactive and complex poly-alcohol containing natural product which is a potent modulator of the calcium release channel [104,105]. In 2016, Reisman's group reported a highly efficient way to rapidly build the carbon framework of ryanodol through intramolecular PKR which was promoted by the rigidity of the bicyclic conformation [106]. Starting from *S*-pulegone, the PK precursor **1** could be achieved after seven steps of transformation. In their promising reaction protocol, submitting **1** with 1 mol% [RhCl(CO)2]<sup>2</sup> under an atmosphere of CO afforded enone **2** in an 85% yield as a single diastereomer. More impressively, the efficient protocol could be performed on the multi-gram scale and provided a 5.7 g of PK product (Scheme 7).

**Scheme 7.** Reisman's total synthesis of (+)-ryanodol.

Tetramethyl thiourea (TMTU) has proven to be an efficient additive in the PKR based on Yang's previous investigations [66]. In 2017, they developed a Co–TMTU catalyzed PKR and 6π electrocyclization tandem reactions to construct the highly strained core skeleton of presilphiperfolanols and related natural products [107,108]. Treatment of **3** with a catalytic amount of [Co2(CO)8] (0.2 equiv.) and TMTU (1.2 equiv.) in benzene resulted in the rapid construction of the tricyclic scaffold **5** with great regio- and stereochemical control in a 94% yield through one single operation. Most recently, they applied this PKR model to the synthesis of 4-desmethyl-rippertenol and 7-epi-rippertenol [109] (Scheme 8).

π

π

**Scheme 8.** Yang's concise synthesis of presilphiperfolane core.

In the total synthesis of the potent antibiotic compounds (−)-crinipellin A and (−)-crinipellin B reported by Yang et al. [97], the fully functionalized tetraquinane core was achieved by a novel thiourea/palladium-catalyzed PKR. They implemented two PKRs in their synthetic strategy with the first being a conversion of **6** into **7** with a 40% yield and 98% *ee* after crystallization. As generally proved, the electron-deficient alkyne is not a perfect ligand for Co2(CO)8, gradual warming is essential for constructing the desired enyne/Co2(CO)<sup>6</sup> complex. The other PKR allows the concise formation of the tetraquinane **10**. Treatment of **8** in the presence of NaHCO<sup>3</sup> as the base provided the desired tetraquinane core **10** in a 61% yield, with the undesired isomer suppressed to a 16% yield (Scheme 9).

**Scheme 9.** Yang's total synthesis of crinipellins.

In 2018, Yang's group described a stereoselective construction of the CDEFGH ring system of lancifodilactone G acetate and a 28-step asymmetric total synthesis [110,111]. They performed an intramolecular PKR for the construction of the sterically congested F ring. In their model study, the authors observed that the butynoic ester was effective for the regio- and stereoselectivity in constructing the cyclopentenone ring system bearing two chiral centers. The developed well-orchestrated PKR facilitated the stereoselective synthesis of **14** from enyne **13** (Scheme 10).

**Scheme 10.** Yang's asymmetric total synthesis of lancifodilactone G acetate.

Li et al. reported the first total synthetic work of hybridaphniphylline B featuring a late-stage intermolecular Diels–Alder reaction [112]. They implemented a PKR and C=C bond migration strategy to achieve the key intermediate **17**. Through the investigation of Pauson-Khand conditions, it is determined that MeCN is an effective accelerator to transform the alkyne dicobalt complex into the desired product, which was depicted the same as Pauson's work [113]. Under this condition, the two PKR products **16** and **16'** were constructed in a 73% yield with the ratio of ca. 2.4:1. Then, submitting the mixture to K2CO3/TFE realized the C=C bond migration and gave the more substituted enone **17** (Scheme 11).

**Scheme 11.** Li's total synthesis of hybridaphniphylline B.

Liang et al. described a concise total synthesis towards (−)-indoxamycins A and B, a novel class of polyketide natural products, which contain a highly congested cage-like carbon skeleton featuring six contiguous chiral centers [114]. The key step for rapidly constructing the framework bearing a quaternary carbon was an intramolecular PKR. Enyne **18** was converted into the 5,5,6-tricyclic compound **19** smoothly with a 74% yield, which could be further transformed into the target natural products (Scheme 12).

**Scheme 12.** Liang's total synthesis of (−)-indoxamycins A and B.

Guaianolide sesquiterpenes represent a particularly prolific class of terpene natural products, which have attracted biological and chemical communities for decades given their extensive documented therapeutic properties and fascinating chemical structures. Recently, the cobalt- mediated intramolecular PKR was applied in the total synthesis of sinodielide A and ent-absinthin by Mainone et al. [115]. Ester **20**, converted from (−)-linalool via deprotonation and a subsequent reaction with the mixed anhydride of 2-butynoic acid, underwent a smooth PKR reaction using Co2(CO)<sup>8</sup> and resulted in strained bicyclic lactone **21** (65% yield, 5:2 d.r.), which enabled concise and collective total syntheses of guaianolide sesquiterpenes (Scheme 13).

**Scheme 13.** Maimone's allylative approaches to the synthesis of complex guaianolide sesquiterpenes.

− σ − − σ − Yang et al. recently described the first asymmetric total synthesis of (−)-spirochensilide A featuring a tungsten-mediated cyclopropene-based PKR to install the quaternary chiral center [116]. Initially, they attempted various conditions to construct the cyclopentenone motif in **24** but all proved in vain presumably due to the low reactivity of enyne **23** and its steric rigidity. Recognizing the inherent of a chloride, they employed it as an σ electron-withdrawing group to promote polarization and reduce the activation barrier, with the idea in hand they prepared chloroenyne **25**. However, reaction conditions screening only resulted in the undesired ring-closing compounds **26** and **27,** respectively, which was generated by an Rh-catalyzed carbonylative C-H insertion and a double bond isomerization followed by a PKR. Then, they considered taking advantage of cyclopropene's inherent strain and altered the pathway to construct enyne **28**. After an investigation of many conditions, the W(CO)3(MeCN)3, Ni(COD)2/bipy, and Mo(CO)3(DMF)3-catalyzed PKR could lead to the formation of the desired **29a**, which could be further transformed into (−)-spirochensilide A (Scheme 14).

**Scheme 14.** Yang's asymmetric total synthesis of (−)-spirochensilide A.

− Very recently, Yang and Snyder's group both reported their total synthesis towards the challenging target (+)-waihoensene [98,99], which contains four contiguous quaternary carbon centers. In their strategies, they all involved a diastereoselective Conia-ene type reaction and an intramolecular PKR. The polycyclic skeleton of Waihoensene was achieved by the Co2(CO)8-mediated PKR under CO atmosphere (Scheme 15).

**Scheme 15.** Yang's and Snyder's total synthesis of (+)-waihoensene.

−

(−)-Conidiogenone B, (−)-conidiogenone, and (−)-conidiogenol feature a highly strained 6/5/5/5 tetracyclic core and 6-8 consecutive stereocenters. The concise total syntheses have been accomplished by Zhai et al. [117]. The key linear triquinane **38** was constructed as a single diastereomer in a 71% yield via a tandem Nicholas and amine-N-oxide-promoted PKR from **37** with the borane-methyl sulfide complex as the hydride source (Scheme 16).

**Scheme 16.** Zhai's total synthesis of (−)-conidiogenone B.

#### *2.2. Construction of 5,6-Bicyclic Ring Systems*

Clark et al. elucidated an efficient 12-step synthesis of the marine alkaloid (−)-nakadomarin A [118], which contains a unique hexacyclic structure featuring fused 5-, 6-, 8-, and 15- membered rings and exhibits cytotoxicity against murine lymphoma L1210 cells, antimicrobial and inhibitory activity against cyclin-dependent kinase 4. The fused bicyclic enone **40** was constructed in a good yield and with an excellent *ee* value using the asymmetric cobalt-catalyzed PKR, which was developed by Hiroi et al. earlier before (Scheme 17).

**Scheme 17.** Clark's total synthesis of (−)-nakadomarin A.

In the Hao et al. studies toward the 10 step-synthesis of a novel limonoid perforanoid A [119], they investigated Rh-catalyzed intramolecular PKR to build the cyclopentenone ring. Under their optimum conditions, treatment of **42** in toluene for 3 h at a reaction concentration of 8 mM with [Rh(CO)2Cl]<sup>2</sup> (7 mol%) as the catalyst gave **43** in 85% as a single isomer (Scheme 18).

**Scheme 18.** Hao's asymmetric total synthesis of perforanoid A.

Zard, Takayama, and Mukai groups have explored the diastereoselective study of intramolecular PKR in the context of Lycopodium alkaloids syntheses [120–122]. Based on their previous study, Trauner et al. used a similar strategy to synthesize enone **46** with the desired stereoselectivity,

−

−

which was proposed through a chair-like conformation of intermediate **45** ensuing the bicycle [4.3.0] nonenone [123] (Scheme 19).

**Scheme 19.** Trauner's expedient synthesis of (+)-lycopalhine A.

− Nakamura et al. have accomplished the stereoselective total synthesis of (+)-marrubiin involving a CyNH2-promoted PKR and subsequent oxidative cleavage of the resultant cyclopentenone ring [124,125]. According to their DFT studies, the irreversible olefin insertion step is critical to the stereochemistry of PKR. The steric interaction could be avoided through a trans-fused chair−boat-like TS and therefore the exclusive isomer **48** was afforded (Scheme 20). −

− **Scheme 20.** Nakamura's total synthesis of (+)-marrubiin and (−)-marrulibacetal.

−

μ

− − Yu et al. have developed an Rh(I)-catalyzed [3 + 2 + 1] cycloaddition of 1-ene/yne−vinylcyclopropanes (VCPs) and CO, which was used to construct 5,6-bicyclic advanced intermediate **50** from yne-VCP (±)-**49** [126]. The advanced intermediate **50** can be transformed into Gao's intermediate for the formal synthesis of gracilamine [127]. This cycloaddition provided a solution to construct the bridgehead quaternary carbon center. The diastereoselectivity was realized by the repulsion between the OTBS (TBS = *t*-butyldimethylsilyl) group and the vinyl moiety (Scheme 21).

**Scheme 21.** Yu's formal synthesis of gracilamine.

In the synthesis of calcitriol, the active form of vitamin D3, Mourino et al. utilized the NMO promoted PKR to form the 5,6-bicyclic core **52** in a diastereoselective way [128]. Intermediate **52** underwent Si-assisted allylic substitution and some other transformations to complete the synthesis of calcitriol (Scheme 22).

**Scheme 22.** Mourino's total synthesis of calcitriol.

Khan et al. delineated the collective total synthesis of iridolactones [129]. The newly constructed iridoid framework **54** was accomplished by a diastereoselective intramolecular PKR [130]. With the key intermediate **55** in hand, they demonstrated a general and simple route to access structurally divergent iridolactones (Scheme 23).

**Scheme 23.** Khan's total synthesis of several iridolactones.

μ μ A fawcettimine-type Lycopodium alkaloid (+)-sieboldine A contains an unprecedented fused tetracyclic skeleton and has been found to inhibit acetylcholinesterase with an IC<sup>50</sup> value of 2.0 µM [131]. Mukai et al. have applied PKR to afford the bicyclo [4.3.0] nonenone derivative **57** with high stereoselectivity with an *ee* value of 93% in their total synthesis of (+)-sieboldine A [132] (Scheme 24).

**Scheme 24.** Mukai's enantioselective total synthesis of (+)-sieboldine A.

Since the hPKR variant is much less reported, Zhai et al. applied an interesting hPKR in the formal synthesis of (±)-aplykurodinone-1 [133]. The tricyclic framework **59** has been constructed with a 60% yield through expeditiously one-pot intramolecular hPKR followed by the desilylation sequence. The hPKR is relatively rare to be found in natural product synthesis, and this application provided worthwhile insights for expanding the scope and boundaries (Scheme 25).

**Scheme 25.** Zhai's formal synthesis of (±)-aplykurodinone-1.

(−)-Sinoracutine, isolated from *Stephania cepharantha* in 2010 [134], proves to be a promising template for new neuroprotective reagents intervention as it was shown to increase cell viability against hydrogen peroxide-induced damage in PC12 cells [135]. Structurally, it features an unprecedented tetracyclic 6/6/5/5 skeleton that bears an N-methylpyrrolidine ring fused to acyclopentenone. In the first total synthesis of (−)-sinoracutine [136], Trauner et al. utilized intramolecular PKR under the oxidative condition as a key transformation to construct the tricycle product **61** from an enyne precursor **60**. The reaction was carried out in the presence of N-oxide dihydrate together with Co2(CO)8. The resulting tricyclic product **61** allows the concise total synthesis of (−)-sinoracutine with several steps of transformations, including a Mandai–Claisen reaction to install the quaternary stereocenter (Scheme 26).

**Scheme 26.** Trauner's enantioselective synthesis and racemization of (−)-sinoracutine.

Cyanthiwigin type diterpenes are biologically important marine natural products mostly isolated from marine sponges *Epipolasis reiswigi* and *Mermekioderma styx*. Particularly, cyanthiwigin C and F show medium cytotoxicity against A549 cell lines [137]. In 2019, Yang et al. reported the total synthesis of 5-epi-cyanthiwigin I [138]. The key [5–6–7] tricarbocyclic fused core structure was constructed via a well-orchestrated Co-mediated intramolecular PKR, which has two cis-configured all-carbon quaternary chiral centers and an isopropyl group. Enyne **62** could be transformed into the tricyclic product **63** as the sole isomer in a 70% yield in the presence of a stoichiometric amount of Co2(CO)<sup>8</sup> combined with NMO as the additive (Scheme 27).

**Scheme 27.** Yang's stereoselective total synthesis of (±)-5-epi-cyanthiwigin I.

Lycopodium alkaloids are neuropharmacologically valuable scaffolds for central nervous system drug discovery. Takayama et al. reported an asymmetric total synthesis of lycopoclavamine A via a strategy involving a stereoselective PKR and a stereoselective conjugate addition to construct a quaternary carbon center at C12 [139]. The cobalt-mediated intramolecular PKR afforded a desired bicyclic enone **65** in a high yield as well as good diastereoselectivity (Scheme 28).

α β γ

−

−

**Scheme 28.** Takayama's asymmetric total synthesis of lycopoclavamine-A.

− Complex sesterterpenoids astellatol and astellatene were isolated from *Aspergillus stellatus* in 1989 [140], which feature highly congested and unusual pentacyclic skeletons and contain a unique bicyclo[4.1.1]octane moiety consisting of ten stereocenters and a cyclobutane containing two quaternary centers. In the total syntheses of (+)-astellatol and (−)-astellatene reported by Xu et al. [141], an intramolecular PKR was exploited to construct the 6,5-bicyclic core embedded in the right-wing scaffold. The desired hydrindane skeleton **67** was generated from enyne **66** with a promising yield and diastereoselectivity at the C7 quaternary carbon center (Scheme 29). − −

**Scheme 29.** Xu's asymmetric total synthesis of (+)-astellatol.

α β γ α β γ Porée et al. reported an elegant synthesis of allosecurinine, utilizing the W(CO)6-promoted oxa-hetero-Pauson–Khand reaction (oxa-hPKR) in the late stage. Despite a low yield, the results constituted the first example of applying the W(CO)<sup>6</sup> complex in hPKR, constructing tetracyclic securinega alkaloid featuring an α, β-unsaturated γ-lactone moiety [142] (Scheme 30). α β γ

− − **Scheme 30.** Porée's enantioselective synthesis of (−−)-allosecurinine.

The calyciphylline B-type alkaloids with a unique hexacyclic framework exhibited a variety of important pharmacological potentials. In the synthesis of daphlongamine H, Sarpong et al. used a late-stage cobalt-mediated PKR to accomplish the 6,5-bicyclic segment. The *R* configuration of C6 in the PKR enabled the desired 10-H ααorientation in the PK product **70** [143] (Scheme 31).

**Scheme 31.** Sarpong's total synthesis of (−)-daphlongamine H. **Scheme 31.** Sarpong's total synthesis of (−)-daphlongamine H.

μ

#### *2.3. Construction of 5,7 Bicyclic Ring Systems*

α

Thapsigargin (Tg1) and its analogs are biologically important candidates as potent inhibitors of the SERCA-pump protein, with the potential of application in a variety of medicinal areas [144,145]. Numerous attempts have been reported on the total synthesis of this bioactive molecule [146–148]. In 2019, Sorin et al. developed a linear route towards the core of Tg1, which features an allene-yne Rh(I)-catalyzed Pauson-Khand annulation (APKR) as key transformation [149]. The allene-yne precursor was generated from chiral propargylic alcohol **71**, which underwent a Ti(II) mediated reductive coupling to form diol **72**. The allene-yne product **73** was elaborated in several steps. The central feature was identified to be the Rh(I)-catalyzed Pauson-Khand annulation (APKR), resulting in the efficient synthesis of the Tg 1 framework bearing an enol ether moiety in a 71% yield (Scheme 32).

−

**Scheme 32.** Sorin's synthesis of a thapsigargin core.

μ Bufospirostenin A, isolated in 2017 from the toad *Bufo bufo gargarizans*, is an unusual steroid with rearranged A/B rings, possessing a cardioactive effect and promoting blood circulation through causing a 43% inhibition of Na/K ATPase (NKA) at 25 µM [150]. Very recently, a unique intramolecular rhodium-catalyzed PKR of an alkoxyallene-yne substrate was applied to construct the key [5–7] A-B ring system in the first total synthesis of bufospirostenin A reported by Li et al. [151]. Generated from Hajos-Parish ketone, alkyne **74** underwent 1,2-addition to afford precursor **75,** which further yielded tetracyclic product **76** catalyzed by [RhCl(CO2)]<sup>2</sup> in the presence of a balloon pressure of CO in toluene with a high yield (85%). This work represented the first example of an intramolecular Pauson−Khand reaction of an alkoxyallene-yne in natural product synthesis (Scheme 33).

#### *2.4. Construction of Macrocycles*

The synthesis of macrocyclic natural products and related structures through a direct C-C bond formation is challenging. Widely applied methodologies include ring-closing metathesis (RCM), Nozaki-Hiyama-Kishi (NHK) reaction, and intramolecular Diels-Alder reactions. PKR has been used and confined in the synthesis of medium-sized rings (up to 11 atoms) [152,153], thus not yet been extended to macrocycles (Scheme 34).

−

−

**Scheme 33.** Li's asymmetric total synthesis of bufospirostenin A.

**Scheme 34.** Synthetic strategy for medium-sized rings.

Spring et al. reported their investigation of PKR for macrocyclization of a template substrate **79 [154]**. After fluorous solid-phase extraction (F-SPE), optimized PKR conditions produced a mixture of structurally unusual macrocycles containing a cyclopentenone motif; these can be separated by HPLC, but they used the mixture in the modified phase (Scheme 35).

**Scheme 35.** Spring's synthetic strategy for structurally diverse and complex macrocycles.

#### **3. Summary and Outlook**

The extraordinary impact of the Pauson-Khand reaction on synthetic methods is still recognized nowadays, and attempts are currently undertaken to further extend the use of various metal-assisted chemistry to environmentally friendly processes within the strongly invoked green chemistry paradigm. The PKR, especially when conducted in an intramolecular fashion, has been widely used as a convenient and powerful tool for the construction of cyclopentenone structural units in natural product synthesis. Though the classical PK cycloaddition has the shortcoming that requires high temperatures and a long reaction time, chemists have developed a range of promoters (TMTU/NMO/TMAO = trimethylamine *N*-oxide, etc.) to circumvent this situation. Moreover, PKR has the merit of well tolerance to a broad variety of functional groups, such as alcohols, ethers, thioethers, esters, nitriles, amines, amides, sulfonamides, etc. With the impressive developments in the catalytic version of

the Pauson–Khand reaction, the application will be more facilitated. Additionally, 4,5-fused bicycles afforded by intermolecular PKR patterns are still called for intensive studies.

**Author Contributions:** Conceptualization, S.C. and C.J.; data collection S.C. and C.J.; writing—original draft preparation, S.C. and C.J.; writing—review and editing, S.C., C.J., N.Z., Z.Y. and L.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the National Key Research and Development Program of China (grant no. 2018YFC0310905); National Science Foundation of China (grant nos. 21632002 and 21801123); and Shenzhen Basic Research Program (grant nos. 2019SHIBS0004, JCYJ20170818090044432, and JCYJ20180302180215524).

**Acknowledgments:** Research activities in related areas in Yang's lab are financially supported by the National Key Research and Development Program of China (grant no. 2018YFC0310905); National Science Foundation of China (grant nos. 21632002 and 21801123); and Shenzhen Basic Research Program (grant nos. 2019SHIBS0004, JCYJ20170818090044432, and JCYJ20180302180215524).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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### *Review* **Radical Carbonylative Synthesis of Heterocycles by Visible Light Photoredox Catalysis**

#### **Xiao-Qiang Hu 1, \* , Zi-Kui Liu <sup>1</sup> and Wen-Jing Xiao 2, \***


Received: 1 August 2020; Accepted: 11 September 2020; Published: 14 September 2020

**Abstract:** Visible light photocatalytic radical carbonylation has been established as a robust tool for the efficient synthesis of carbonyl-containing compounds. Acyl radicals serve as the key intermediates in these useful transformations and can be generated from the addition of alkyl or aryl radicals to carbon monoxide (CO) or various acyl radical precursors such as aldehydes, carboxylic acids, anhydrides, acyl chlorides or α-keto acids. In this review, we aim to summarize the impact of visible light-induced acyl radical carbonylation reactions on the synthesis of oxygen and nitrogen heterocycles. The discussion is mainly categorized based on different types of acyl radical precursors.

**Keywords:** radical carbonylation; acyl radical; visible light photocatalysis; heterocycles

#### **1. Introduction**

Carbonyl-containing compounds, such as ketones, esters and amides, widely exist in numerous biologically important natural products, functional materials as well as pharmaceuticals [1–5]. The development of efficient methods toward synthesis of these substantial compounds has been intensively pursued by synthetic chemists over the past decades. Radical carbonylation promoted by transition metals (Pd, Mn, Co, Ni, Ru, Rh etc.), external oxidants or thermal initiation has been well-established for the preparation of carbonyl compounds with high efficiency [6–12]. Additionally, light-induced radical carbonylation reaction affords an alternative platform for the assembly of carbonyl motifs [13–17]. The pioneering examples are typically mercury and polyoxotungstate-photosensitized alkane carbonylation, metal-carbonyl catalyzed radical carbonylation and radical/Pd-combined carbonylation. Despite these impressive advances, the requirement of high-energy UV irradiation, poor selectivity or low efficiency profoundly limits their broad applications in practical synthesis.

Visible light photoredox catalysis has emerged as one of the most important techniques in radical reactions by employing an abundant and endlessly renewable solar energy as a driving force [18–30]. Under photocatalytic conditions, various radical species can be formed in a mild and controllable fashion, which enables the precise synthesis of high value-added products. In this context, acyl radicals are commonly generated by the addition of alkyl or aryl radicals to carbon monoxide (CO) or from single electron transfer (SET) conversion of aldehydes, carboxylic acids, anhydrides, acyl chlorides or α-keto acids (Scheme 1) [31]. In this review, we mainly summarize recent advances in the field of visible light-induced radical carbonylative synthesis of oxygen and nitrogen heterocycles with an emphasis on the catalytic system, scope and reaction mechanism. The principal achievements are partitioned into the sections organized based on different acyl radical precursors. Transition metal-catalyzed radical

carbonylation and atom transfer radical carbonylation have been comprehensively reviewed before and will not be discussed here [32,33].

**Scheme 1.** Acyl radical carbonylation reactions in the synthesis of heterocycles.

#### **2. Carbon Monoxide (CO)-Mediated Radical Carbonylation**

Carbon monoxide (CO), as a cheap and readily available carbonyl source, has been extensively used in radical carbonylations [34,35]. In 2014, Xiao and colleagues reported a visible light-induced photocatalytic alkoxycarboxylation of aryldiazonium salts with alcohols under the CO pressure of 80 atm (Scheme 2) [36]. A range of structurally diverse benzoates was obtained in moderated to good yields. Notably, natural chiral alcohols such as N-benzoyl *L*-(+)-prolinol, (-)-menthol and methyl *D*-(-)-mandelate were compatible with this carbonylation reaction. When *ortho*-allyl- or *ortho*-propargyl-substituted benzenediazoniums were used, the resultant dihydrobenzofuran **11d** and benzofuran **11e** were formed in 63% and 58% yields, respectively. Almost at the same time, the group of Wangelin achieved the same reaction using eosin Y as a cheap photosensitizer [37]. Importantly, a lower pressure of CO (50 atm) was sufficient in this reaction. These two findings opened new avenues for the development of radical carboxylation reactions.

**Scheme 2.** Alkoxycarboxylation of aryldiazonium salts with alcohols.

It is believed that a visible light-induced radical carbonylation pathway would be involved in this reaction, as accounted for by control experiments and density functional theory (DFT) calculations (Scheme 3). Upon irradiation with blue LEDs, the photocatalyst PC initially undergoes a photoexcitation process to give a long-lived excited species PC\*. Then, a single-electron reduction of aryldiazonium salt **9** by PC\* produces the intended aryl radical intermediate **9-A**. Thereafter, radical **9-A** is rapidly trapped by CO to generate the key acyl radical **9-B**, which can be easily oxidized by PC <sup>+</sup> to achieve the benzylidyneoxonium **9-C**, thus completing the photocatalytic cycle. Subsequently, the electronic trapping of **9-C** by alcohols results in the benzoate products.

**Scheme 3.** A plausible mechanism for the alkoxycarboxylation of aryldiazonium salts.

Later, Gu et al. used (hetero) arenes as electrophiles to trap the reactive benzylidyneoxonium intermediates, delivering aryl ketones in moderate yields [38]. Generally, the electron-rich arenes gave better results over electron-deficient substrates, and nitrobenzene failed to give the expected product in the current system. In 2016, Li et al. further extended this strategy to the carbonylation of indoles for the preparation of various indol-3-yl aryl ketones [39]. In addition, by employing readily available arylsulfonyl chlorides as a robust source of aryl radicals, Liang, Li and co-workers achieved the same reaction under a 80 atm CO atmosphere with irradiation by green LEDs [40].

In 2018, a visible light-induced annulative carbonylation of alkenyl-tethered aryldiazonium salts was developed by Polyzos et al. in continuous-flow (Scheme 4) [41]. Under a moderate CO pressure (25 atm), this reaction proceeded smoothly to afford a range of 3-acetate substituted 2,3-dihydrobenzofurans **14** in satisfactory yields with excellent chemo- and regio-selectivity. Moreover, the generality of this transformation can be further extended to the reaction of unsaturated *ortho*-tethered aryldiazonium salts. When 1-butenyloxy- and propargyloxy-substituted aryldiazonium salts were subjected to the optimal conditions, the acetate-functionalized chromane **14f** and benzofuran **14e** were successfully obtained in 72% and 57% yields, respectively. It should be noted that the current continuous-flow protocol drastically shortens the reaction time to 200 s, which enables a preparative scale-up reaction in high efficiency.

**Scheme 4.** Annulative carbonylation of alkenyltethered aryldiazonium salts.

In 2015, Xiao and Lu et al. reported an elegant decarboxylative/carbonylative alkynylation of carboxylic acids (Scheme 5a) [42]. Remarkable features of this transformation include mild conditions and high efficiency. The synthetic utility of this methodology was demonstrated by the success of a rapid solar light-driven reaction and 5.0 mmol gram-scale reaction. Unlike the well-established Heck reactions of alkenyl and aryl substrates, the alkyl-Heck reaction is still problematic due to the inherent difficulty in palladium-mediated oxidative addition of electrophilic alkyl reagents and competitive β-hydrogen elimination of the generated alkyl–palladium species. Very recently, Xiao and Lu et al. further disclosed a novel deaminative alkyl-Heck-type reaction by replacing palladium-catalyzed two-electron pathway with a photocatalytic single-electron activation [43]. Katritzky salts acted as the alkyl radical sources in this reaction, which can be easily synthesized from structurally diverse alkyl amines [44–46]. The choice of bases is critical in this reaction and 1,4-diazabicyclo[2.2.2]octane turned out to be the optimal base. Moreover, under a CO pressure of 80 atm, a photostimulated deaminative/carbonylative Heck-type procedure was developed for the construction of α,β-unsaturated ketones in moderate to excellent yields (Scheme 5b). This radical-mediated alkyl-Heck-type protocol provides a new approach to the libraries of alkenes, complementing the current late-stage of palladium-catalyzed Heck reactions. As illustrated in Scheme 5b, under irradiation with blue LEDs, the excited state Ir(III)\* is quickly quenched by Katritzky salt **18** to give a reactive alkyl radical **18-A** along with the formation of Ir(IV)-catalyst. The subsequent reaction of alkyl radical **18-A** with CO produces an acyl radical **18-B**, which then reacts with an alkene to give radical species **19-A**. Finally, the SET oxidation of **19-A** by Ir(IV)-catalyst affords intermediate **19-B**, which undergoes a deprotonation process to give the final enone product. β – – α β

**Scheme 5.** (**a**) Decarboxylative/carbonylative alkynylation of carboxylic acids; (**b**) Photostimulated deaminative alkyl-Heck-type reaction.

A novel photocatalytic aminocarbonylation of cycloketone oxime esters with amines has been discovered by Xiao and Chen (Scheme 6) [47]. The reactive Cu(I) complex derived from CuCl catalyst and N, N, N-tridentate ligand worked as both visible light photocatalyst and carbonylation catalyst in this reaction. Control experiments suggested the necessity of a copper catalyst, ligand and visible light irradiation. Under the standard conditions, a variety of (hetero)aryl amines and alkyl amines reacted with cycloketone oxime esters, yielding the structurally different aminocarbonylation products in moderate to good yields (Scheme 6a). Importantly, the pharmaceutical agent (±)-mexiletine can be converted in this reaction, highlighting the synthetic potential of this methodology. This reaction provides a direct access to diverse cyanoalkylated amides at ambient temperature. –

–

**Scheme 6.** (**a**) Aminocarbonylation of oxime esters; (**b**) Proposed mechanism.

According to the mechanistic studies and literature precedents, two reaction pathways have been proposed by authors (Scheme 6b). Under blue-light irradiation, a single-electron reduction of cycloketone oxime ester **21** by the photoexcited state of LnCu(I)–NHPh complex **22-A**\* (path A) is observed, delivering an iminyl radical intermediate **21-A**. In addition, the cycloketone oxime ester **21** can be also reduced by the ground state of Cu(I)/L<sup>n</sup> catalyst **22-A** due to its redox reactivity (path B). Then, a fast β−C–C bond cleavage of **21-A** leads to the cyanoalkyl radical intermediate **21-B**, which can react with Cu(II)-catalyst to generate a high-valent Cu(III) complex **21-C**. The insertion of a CO molecule into Cu(III)–C bond affords the intermediate **21-D**. Finally, the reductive elimination of **21-D** gives rise to the amide product **23** with the regeneration of Cu(I)-catalyst for the next catalytic cycle.

Very recently, Arndtsen et al. developed an elegant carbonylative coupling reaction of aryl or alkyl halides with some challenging nucleophiles [48]. The active catalysts of this transformation were believed to be the photoexcited state of Pd(0) and Pd(II) species, which can promote the oxidative addition and reductive elimination steps with low energy barriers (Scheme 7a). It was found that the addition of a visible light photocatalyst was not necessary for this reaction. However, in the absence of blue-light irradiation, palladium catalyst or phosphine ligand (DPEphos), no reaction has been observed. A range of nucleophiles such as sterically hindered secondary amines, tertiary alcohols, substituted anilines and even weakly nucleophilic N-heterocycles can be coupled at ambient temperature, producing various important esters, amides and ketones.

–

**Scheme 7.** (**a**) Radical carbonylation of halides; (**b**) Radical carbonylation of organosilicates.

By using organosilicates as alkyl radical precursors, Fensterbank, Ryu, Ollivier and Fukuyama et al. demonstrated a radical carbonylation of various amines for the construction of aliphatic amides under 80 atm pressure of CO (Scheme 7b) [49]. In this reaction, CCl<sup>4</sup> acted as a Cl-atom donor to react with acyl radicals for the in situ formation of acyl chlorides, which then reacted with amines to produce amide products. CBrCl<sup>3</sup> was also suitable for this process, albeit with a lower yield. The pressure of CO has a pronounced effect on this reaction. When a lower CO pressure of 40 atm was used, the chemical yield was significantly decreased. This strategy can be further applied in an intramolecular carbonylation reaction, leading to pyrrolidinone as the sole product. A plausible mechanism is described in Scheme 7b. Under the irradiation by blue LEDs, the excitation of photocatalyst 4-CzIPN delivers 4-CzIPN\*, which initially reacts with organosilicate **27** to give an alkyl radical **27-A** via an oxidative Si–C bond cleavage. The addition of radical **27-A** to CO results in an acyl radical **27-B**, which then abstracts a chlorine atom from CCl<sup>4</sup> to generate acyl chloride **27-C** and trichloromethyl radical. Acyl chloride **27-C** is rapidly trapped by amines to give the amide products. The in situ formed trichloromethyl radical can regenerate the photocatalyst 4-CzIPN through a single electron-transfer process.

Transition metal-catalyzed oxidative carbonylation provides an effective and general platform for the construction of carbonyl compounds [6]. In this type of reactions, a stoichiometric amount of external oxidants is often required for the recyclization of the active Pd(II)-catalyst. Taking the advantage of the fact that O<sup>2</sup> is a green and powerful oxidant, the group of Lei achieved a novel O2-mediated oxidative carbonylation of enamides by merging photoredox catalysis and palladium catalysis under a low CO pressure (Scheme 8a) [50]. It should be noted that the usage of 8 mol% xantphos can chiefly improve yields of the desired products. <sup>31</sup>P NMR experiments suggested that the phosphine ligand would be firstly converted into its oxidized species, thus facilitating the oxidative carbonylation process. This dual catalytic system affords an environmentally benign access to 1,3-oxazin-6-ones.

**Scheme 8.** (**a**) Oxidative carbonylation of enamides; (**b**) Proposed mechanism.

– As described in Scheme 8b, the vinylpalladium intermediate **30-A** is firstly generated from enamide via Pd(OAc)2-promoted C(sp 2 )–H bond activation of enamides. Then, the coordination and insertion of a CO molecule into intermediate **30-A** produce acylpalladium complex **30-B**, which can be transferred into **30-C** in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO). Reductive elimination of **30-C** delivers the final carbonylation product **32** with the formation of Pd(0)-catalyst. The Pd(0)-catalyst can be further oxidized by the photoexcited state of photocatalyst or superoxide anion to the active Pd(II)-catalyst, thus completing the palladium catalytic cycle.

#### **3. Aldehyde-Mediated Radical Carbonylation**

Aldehydes have been served as versatile building blocks in organic synthesis for a long time. In the presence of hydrogen atom transfer (HAT), reagents such as persulfates, *tert*-butyl hydroperoxide (TBHP), quinuclidine and Eosin Y, aldehydes can be easily converted into acyl radical species through a rapid HAT [31,51]. In this section, we mainly discuss the acyl radical reactions of aldehydes for the assembly of oxygen and nitrogen heterocycles. In 2014, Zeng and Xie et al. reported an interesting benzaldehyde-mediated Minisci reaction for the regiospecific acylation of biologically important phenanthridines (Scheme 9) [52]. In this reaction, 2.0 equivalent of (NH4)2S2O<sup>8</sup> was used as the HAT reagent as well as the external oxidant. This catalytic system is especially well-adapted for aromatic aldehydes, giving 6-acylated phenanthridines in moderate yields.

As an attractive alternative to persulfates, the cheap and readily available TBHP can be also used as a good HAT reagent [53]. In 2015, Wang and co-workers independently published an acyl radical-mediated cascade reaction of benzaldehydes and styrenes for the synthesis of α, β-epoxy ketones (Scheme 10) [54]. TBHP was identified to be superior over other traditional oxidants such as K2S2O8, benzoyl peroxide (BPO) and (t-BuO)2. Various styrenes bearing electron-donating and -withdrawing groups performed well, providing α, β-epoxy ketones in generally good yields. Notably, both 1,1-disubstituted alkenes and pentafluorinated alkenes were compatible with this catalytic system. Significantly, this reaction can be easily scaled up for a gram-scale ketone synthesis.

α, β

**Scheme 9.** Benzaldehyde-mediated regiospecific acylation of phenanthridines.

α, β

α, β

**Scheme 10.** Acyl radical-mediated cascade reaction of benzaldehydes and styrenes.

• β α, β Mechanistic studies by radical trapping experiments and analysis of the reaction mixture by high-resolution mass spectroscopy (HRMS) suggested a plausible acyl radical pathway (Scheme 11). At first, an oxidative quenching of the photoexcited Ru 2+\* complex by TBHP gives a *tert*-butoxy radical, which subsequently abstracts a H-atom from benzaldehyde to form the key acyl radical **37-A**. Secondly, the selective addition of radical **37-A** to alkene **36** results in a new C-based radical intermediate **36-A**. At the same time, the oxidation of *tert*-butyl peroxide anion by oxidizing Ru <sup>3</sup><sup>+</sup> complex affords *tert*-butyl peroxide radical and regenerates the ground state of Ru <sup>2</sup><sup>+</sup> catalyst. The rapid radical coupling of *t*-BuOO• with **36-A** delivers β-peroxy ketone **36-B**, which can be detected by HRMS analysis. Finally, under basic conditions, **36-B** undergoes a cyclization process to generate the desired α, β-epoxy ketone product with the elimination of *<sup>t</sup>*BuOH.

**Scheme 11.** Proposed pathway for the radical cascade reaction of benzaldehydes and styrenes.

The group of Salles Jr achieved the same reaction in water with the use of persulfate K2S2O<sup>8</sup> as the oxidant and methylene blue as the organophotoredox catalyst (Scheme 12) [55]. It is noteworthy that O<sup>2</sup> in water plays an important role in this transformation. Lower yields were observed when reactions were conducted in the degassed water or under N<sup>2</sup> atmosphere. Two different types of reactions have been developed, employing only one set of reagents. When styrenes were used as

'

radical acceptors, a visible light-induced epoxyacylation reaction was accomplished. Both aromatic and aliphatic aldehydes were smoothly converted into various epoxyketones in good yields. Interestingly, when nonconjugated olefins were used, the reaction underwent a direct hydroacylation process to form long-chain ketones. In this hydroacylation reaction, only aromatic aldehydes were tolerated. In 2020, the group of Kokotos developed an acyl radical-mediated hydroacylation reaction of alkenes from simple aldehydes under metal-free conditions [56]. Using 4-acyl-1,4-dihydropyridines as acyl radical sources, Xia et al. reported an interesting visible light-induced hydroacylation of alkenes under photocatalyst-free conditions. Additionally, in the presence of a Ni(II)-catalyst, the diacylation reaction was developed [57]. Moreover, Melchiorre et al. achieved an asymmetric acylation reaction of enals for the stereocontrolled construction of 1,4-dicarbonyl products [58].

**Scheme 12.** Visible light-induced acyl radical epoxyacylation of olefins.

' Using the same strategy, in 2017, Hong's group reported an acyl radical-mediated intramolecular epoxyacylation reaction catalyzed by Ru(bpy)3Cl<sup>2</sup> (Scheme 13a) [59]. The investigation of optimum reaction conditions revealed that TBHP was the best HAT reagent. Under optimal conditions, various spiroepoxy chroman-4-one scaffolds and spiroepoxy enaminones could be constructed in moderate yields. The utility was demonstrated by mild conditions, simple operation and broad substrate scope. In addition, the applicability of this transformation can be further extended to the epoxyacylation of benzylic alcohols, albeit with relatively lower yields (Scheme 13b). In the tandem reaction of benzylic alcohols, 8.0 equivalent of TBHP was required for the in situ formation of benzaldehyde intermediates. This transformation is initiated by the generation of an aldehyde that undergoes a sequential H-atom transfer, intramolecular radical cyclization and epoxidation process to produce the final products.

**Scheme 13.** (**a**) Intramolecular radical cylization/epoxyacylation of olefins; (**b**) Epoxyacylation of benzylic alcohols.

In 2018, Itoh and co-workers described an acyl radical-mediated addition/cyclization cascade reaction of ynoates with simple aldehydes by employing benzoyl peroxide (BPO) as the external oxidant and 2-*tert*-butylanthraquinone (2 *<sup>t</sup>*Bu-AQN) as the photocatalyst (Scheme 14a) [60]. More than 20 coumarin derivatives can be synthesized in high efficiency, along with excellent regioselectivity. Notably, it was found that many of coumarin products have good antiproliferative activities against prostate cancer cells. The group of Klussmann developed a facile acyl radical difunctionalization of styrenes with the use of indoles and benzotriazole as nucleophiles (Scheme 14b) [61]. Very recently, a visible light photocatalytic deuteration of formyl groups was achieved by Wang et al. via the acyl radical-mediated H/D exchange strategy [62].

**Scheme 14.** (**a**) Acyl radical cascade reactions of ynoates; (**b**) Acyl radical difunctionalization of styrenes.

In addition, acyl radical-mediated alkynylation, arylation, vinylation and alkylation have been well-developed over the past 10 years. This has been reviewed by Ngai [31] and will not be discussed here.

#### **4. Carboxylic Acids and Their Derivative-Mediated Radical Carbonylation**

Carboxylic acids and their derivatives are promising chemical feedstocks in organic synthesis, and can be easily obtained in great structural diversity both from natural sources and some well-established methods [63–65]. Over the past decades, transition-metal catalyzed two-electron decarboxylative conversions of carboxylic acids have been well investigated toward a wide variety of valuable compounds. Recently, a visible light-driven single-electron transfer strategy has provided an important and new platform for the functionalizations of carboxylic acids and their derivatives. In this context, carboxylic acids and their derivatives can be selectively converted to acyl radicals for the preparation of carbonyl-containing compounds and various heterocycles [66].

The direct conversion of carboxylate groups into acyl radicals is relatively challenging due to their high bond strength (102 kcal/mol). In 2018, Zhu, Xie and co-workers developed a convenient deoxygenative activation of carboxylic acids for the hydroacylation of alkenes by using triphenylphosphine (Ph3P) as the oxygen transfer reagent (Scheme 15a) [67]. Taking advantage of the strong P–O affinity between the Ph3P radical cation and carboxylate anion, the homolytic cleavage of C–O bonds can be achieved to generate acyl radicals under mild photocatalytic conditions. Under the standard conditions, various aromatic acids were well-tolerated, while aliphatic acids proved to be unsuitable for this reaction. In addition, the intramolecular radical cyclization reactions were also investigated to synthesize cyclophane-braced macrocycloketones. Moreover, this methodology can be applied for the 3-step concise construction of the drug zolpidem.

– – –

**Scheme 15.** (**a**) Photoinduced deoxygenative activation of carboxylic acids; (**b**) Proposed mechanism.

The reactions were completely inhibited by radical inhibitors such as 2,6-di-*tert*-butyl-*p*-cresol (BHT) and 2,2,6,6-tetramethyl-1-piperidyloxy (TEMPO). To further verify the origin of O-atom in the byproduct Ph3P=O, <sup>18</sup>O-labeling experiments were investigated, suggesting that the O-atom of Ph3P=O would come from benzoic acids rather than from water. Taking together, a plausible acyl radical mechanism is illustrated in Scheme 15b. Under blue-light irradiation, Ph3P is initially oxidized by the excited state of photocatalyst \*Ir III to generate Ph3P radical cation. The rapid combination of Ph3P radical cation with carboxylate anion **50-A** forms the phosphoranyl radical intermediate **50-B**. This intermediate undergoes a fast β-scission fragmentation and delivers acyl radical **50-C**, which then reacts with alkene to give C-radical **51-A**. A SET reduction of C-radical **51-A** by Ir II -catalyst results in an anion intermediate **51-B**, followed by a protonation process to produce the ketone product **52**.

Almost simultaneously, Doyle and Rovis et al. applied this synthetic strategy in the general deoxygenative reduction of carboxylic acids via photoredox catalysis (Scheme 16a) [68]. Remarkably, both aromatic and aliphatic acids could be selectively converted to aldehydes by careful modification of the phosphine reagent. Ph3P has been identified as a good oxygen transfer reagent for the deoxygenation of aromatic acids, while it was ineffective for the aliphatic acids. It is believed that a more electron-rich phosphoranyl radical species can be formed from Ph3P and aliphatic carboxylic acid, which may undergo a rapid oxidation process to generate a reactive phosphonium intermediate for the acyl transfer reactions. As a result, an electron-deficient Ph2POEt was selected as an optimal reductant for the reduction of aliphatic acids. Particularly, this method also enables conversions of carboxylic acids into cyclic ketones and lactones via intramolecular cyclization reactions of acyl radicals. More importantly, this strategy can be further applied in deoxygenative reduction of benzylic alcohols.

β

**Scheme 16.** (**a**) Photocatalytic deoxygenative reduction of carboxylic acids; (**b**) Deoxygenative deuteration of carboxylic acids.

After that, Xie et al. reported a novel deoxygenative deuteration of carboxylic acids by employing inexpensive D2O as the deuterium source (Scheme 16b) [69]. The usage of a thiol catalyst significantly affects this transformation, which may act as a HAT catalyst to tune the equilibrium with D2O, thus facilitating the formation of deuterated aldehydes. Both aromatic and aliphatic acids were conveniently reduced, delivering deuterated aldehydes in moderate yields with high levels of D-incorporation. The robustness of this methodology was demonstrated by the deuteration of biologically important pharmaceuticals and natural products as well as the downstream construction of D-labeled N-containing heterocycles. In a subsequent investigation, in 2019, Zhu, Xie and co-workers disclosed an interesting deoxygenative arylation of aryl carboxylic acids for the preparation of a broad range of unsymmetrical ketones via a visible light-induced 1,5-aryl migration process [70].

By using the same concept, Chu and Sun et al. achieved an elegant acyl radical-mediated intramolecular cyclization of aromatic acids for the preparation of various dibenzocycloketones (Scheme 17) [71]. Methylene blue was the optimal photocatalyst and O<sup>2</sup> as a green oxidant. A range of dibenzocycloketone derivatives were produced in good yields under metal-free conditions. Shortly thereafter, an intermolecular hydroacylation of styrenes was discovered by Doyle's group, affording various dialkyl ketone products [72]. The key to the success of this protocol was the rational selection of a phosphine reagent for the generation of acyl radicals. The electron-rich PMe2Ph with a low oxidation potential was the best choice, which could outcompete the side reactions of alkene substrates. In 2020, Wang and co-workers disclosed a convenient deoxygenation/defluorination cascade reaction for the assembly of γ, γ-difluoroallylic ketones from α-trifluoromethyl alkenes and aryl carboxylic acids. Phenylacetic acids were also tolerated well, while other simple aliphatic carboxylic acids were not compatible with this reaction system [73].

Doyle's

of γ, γ

**Scheme 17.** Acyl radical-mediated intramolecular cyclization of aromatic acids.

The in situ generated anhydride from carboxylic acid could be engaged as an effective acyl radical precursor. In 2015, the group of Wallentin developed an interesting acylarylation cascade reaction of aromatic carboxylic acids and methacrylamides for the preparation of structurally diverse 3, 3-disubstituted 2-oxindoles (Scheme 18a) [74]. The transient anhydrides were believed to be formed from carboxylic acids and dimethyl dicarbonate (DMDC). The choice of visible light photocatalyst plays an important role in this reaction, and only strongly reducing *fac*-Ir(ppy)<sup>3</sup> can efficiently promote this transformation. For electron-rich benzoic acids, the increase in catalyst loading and reaction time were usually required due to their relatively low reactivity. Under optimal conditions, a wide range of 3, 3-disubstituted 2-oxindoles was obtained in a mild manner. The synthetic value was described by the straightforward synthesis of hexahydropyrrolo[2,3-b]indole unit **66e**, which exists widely in many natural products. Similar strategies have been further applied in the hydroacylation of alkenes, reduction of carboxylic acids and deoxygenative radical cyclization [75–78].

–

**Scheme 18.** (**a**) Acylarylation reaction of aromatic carboxylic acids and methacrylamides; (**b**) Acyl radical-mediated difunctionalization of olefins.

Rather than the use of in situ formed anhydride intermediates, Wallentin and co-workers directly employed symmetric anhydrides as acyl radical precursors for the difunctionalization

−

C−C bonds and one C–

of olefins (Scheme 18b) [79]. Two different types of reactions have been developed, including radical acylarylation of N-arylacrylamides and acylation/semipinacol rearrangement of allylic alcohol derivatives. This protocol has been established as a powerful entry to the construction of oxindoles and 1,4-diketones under mild conditions.

A plausible acyl radical addition/intramolecular cyclization mechanism is proposed. In the presence of 2,6-lutidine, the in situ generation of an anhydride intermediate was achieved from benzoic acid and dimethyl dicarbonate (DMDC), which can be reduced by the photoexcited Ir III \*-catalyst (*E*1/<sup>2</sup> (IrIV/\*Ir III ) = −1.73V vs SCE) to form the key acyl radical **50-C** (Scheme 19). Subsequently, the radical **50-C** selectively reacts with olefin **65** to give a C-radical intermediate **65-A**. Finally, the radical **65-A** undergoes a single-electron oxidation and aromatization sequence, producing the oxindole products **66** along with the ground-state of the photocatalyst. −

**Scheme 19.** Plausible mechanism for the acyl radical-mediated acylarylation reaction.

In addition, acyl thioesters are readily available and could be served as a source of acyl radicals. The group of Gryko discovered an unprecedented vitamin B12-catalysed Giese-type acylation of electron-deficient olefins by using 2-S-pyridyl thioesters as acyl radical precursors [80]. An indirect approach to generate acyl radicals from thioesters has been developed by McErlean and co-workers (Scheme 20) [81]. This reaction avoids the use of organo-tin reagent and high-energy UV light irradiation. Under mild photocatalytic conditions, diverse chromanones and indanone derivatives can be synthesized in moderate yields. The synthesis of clinical agent donepezil **72** further demonstrates the potential utility of this reaction.

**Scheme 20.** Acyl thioesters-mediated acyl radical intramolecular cylization reaction.

Acyl chlorides are abundant and highly active acyl radical precursors. In 2017, Xu et al. developed a radical cascade reaction of N-methyl-N-phenylmethacrylamides with aroyl chlorides for the synthesis of various quaternary 3,3-dialkyl 2-oxindole derivatives (Scheme 21a) [82]. In this reaction, aliphatic acyl chlorides have been unsuccessful substrates due to their low reduction potentials. The same group further expanded this concept to the cascade reaction of 1,7-enynes with aroyl chlorides, providing various fused pyran derivatives (Scheme 21b) [83]. This reaction could be scaled up to 4 mmol, albeit with a slightly lower yield.

**Scheme 21.** (**a**) Visible light photocatalytic cascade reaction of N-methyl-N-phenylmethacrylamides with aroyl chlorides; (**b**) Cascade reaction of 1,7-enynes with aroyl chlorides; (**c**) Aroylchlorination reaction of 1,6-dienes.

C−C bonds and one C– Recently, Xu and co-workers established a novel photocatalytic aroylchlorination reaction of 1,6-dienes for the synthesis of highly valuable polysubstituted pyrrolidines (Scheme 21c) [84]. Two C−C bonds and one C–Cl bond can be rapidly constructed in a one-pot process. The rational choice of photocatalysts was found to be the key factor of this reaction. Only *fac*-Ir(ppy)<sup>3</sup> proved to be capable of promoting this reaction. Other commonly used photocatalysts such as Ru(bpy)3Cl2, eosin Y and Ir(ppy)2(dtbbpy)PF<sup>6</sup> were ineffective. Consistent with their previous works, alkyl chlorides were not compatible with this condition. In addition, Oh et al. reported a facile Friedel−Crafts acylation of alkenes, allowing synthesis of various β-chloroketones under mild photocatalytic conditions [85].

A broad array of 3-acylspiro[4,5]-trienone scaffolds was synthesized by Tang's group through a photocatalytic tandem reaction of N-(*p*-methoxyaryl)propiolamides with acyl chlorides (Scheme 22a) [86]. This reaction features a broad scope with high selectivity. It was found that a high temperature of 100 ◦C and 2.0 equivalent of H2O are essential for this reaction. <sup>18</sup>O-labeled experiments indicated that the oxygen atom of the newly generated carbonyl group mainly comes from H2O. The same strategy has been further applied for the preparation of 3-acylcoumarins via acyl radical-mediated cyclization of alkynoates by visible light photoredox catalysis (Scheme 22b) [87]. Very recently, Tang et al. developed an acyl radical cyclization of N-propargylindoles for the construction of various important pyrrolo[1,2-*a*]indole skeletons [88]. An acyl radical proved to be the key intermediate in this reaction.

β

Friedel−Crafts

'

**Scheme 22.** (**a**) Acyl radical cascade cylization of N-(*p*-methoxyaryl)propiolamides; (**b**) Cylization of alkynoates.

Recently, Xuan and Wang et al. developed an elegant photocatalytic acyl radical cyclization of 2-(allyloxy)-benzaldehydes with aroyl chlorides (Scheme 23a) [89]. The unactivated C=C bonds acted as acyl radical acceptors in this process. It was observed that the base is crucial to the reaction efficiency. 2,6-lutidine turned out to be the best base. Under the standard conditions, a series of 2-(allyloxy)-benzaldehydes reacted smoothly with aroyl chlorides to give various chroman-4-one skeletons in moderate yields. More importantly, the chromanone products could be easily converted to other important heterocycles in one-step process, such as benzofuranone and 2-phenyl-4*H*-thieno[3,2-c]chromene.

**Scheme 23.** (**a**) Radical cyclization of 2-(allyloxy)-benzaldehydes with aroyl chlorides; (**b**) Proposed mechanism.

α

–

–

α

α

A series of fluorescence quenching experiments were investigated to gain insights into the reaction mechanism, which indicated that the excited state of photocatalyst was oxidatively quenched by benzoyl chloride. As described in Scheme 23b, under blue-light irradiation, benzoyl chloride is initially reduced by the photoexcited IrIII\* via a single electron transfer, producing the key acyl radical intermediate (Scheme 23b). Then, the selective addition of acyl radical to the unactivated C=C bond affords a C-based radical **83-A**, which then reacts with the carbonyl group to give the O-centered radical intermediate **83-B**. Radical **83-B** undergoes a 1,2-H migration/SET oxidation sequence to give the carbon cation intermediate **83-D**, finishing the visible light photocatalytic cycle. Finally, under basic conditions, intermediate **83-D** proceeds a deprotonation process to give the chroman-4-one product.

#### **5. Miscellaneous Radical Carbonylation**

The single-electron oxidative decarboxylation of α-keto acids provides an alternative method to form acyl radicals [90–92]. In 2014, Lei and Lan et al. reported an interesting decarboxylative amidation of α-keto acids (Scheme 24a) [93]. One impressive feature of this transformation is that O<sup>2</sup> worked as the oxidant. A variety of α-keto acids reacted well with anilines, furnishing the final products in generally good yields. For aliphatic amines, 5–10 equivalents of amines were required to achieve good yields. More significantly, this reaction can be further utilized in the construction of N-containing heterocycles such as benzothiazole, benzoxazole and benzimidazole. Visible light irradiation of Ru(II)-catalyst delivers the excited Ru(II)\* species via metal-to-ligand charge transfer (MLCT), which is reductively quenched by an amine **86** to give intermediate **86-A**. Then, O<sup>2</sup> acts as an oxidant to regenerate the ground state of Ru(II)-catalyst along with the formation of the superoxide radical anion. The superoxide radical anion further reacts with **85-A** to give radical intermediate **85-B**, which undergoes a decarboxylative process to afford acyl radical **86-B**. Subsequently, this acyl radical reacts with an amine to generate intermediate **86-C**, which then undergoes a SET process to give the amide product. Chu et al. disclosed an interesting palladium-catalyzed decarboxylation coupling/intramolecular cyclization sequence for the formation of 4-aryl-2-quinolinone derivatives (Scheme 24b) [94]. The author further elaborated its potential applicability in the rapid synthesis of the hepatitis B virus (HBV) inhibitor in an atom economy manner.

In 2016, Wang et al. demonstrated an elegant hypervalent iodine (BI–OAc)-mediated decarboxylative cyclization reaction under photocatalyst- and oxidant-free conditions (Scheme 25a) [95]. The reaction produces various oxindoles in moderate to good yields. Mechanistic studies suggested that a cascade decarbonylation, radical addition and cyclization pathway were involved in this reaction (Scheme 25b). The reaction of α-keto acid with BI–OAc results in the hypervalent iodine intermediate **91-A**. Under blue LED irradiation, the homolytic cleavage of **91-A** generates iodanyl radical **91-B** and acyl radical **50-C**. Then, the acyl radical further reacts with acrylamide **65** to give intermediate **65-B**, followed by a hydrogen atom abstraction process to afford the desired product **66** along with the formation of intermediate **91-C**. The intermediate **91-C** may react with α-keto acid to give the hypervalent iodine intermediate **91-A** for the next catalytic cycle.

Using (NH4)2S2O<sup>8</sup> as an oxidant, Hu, Huo and Su et al. developed an eosin B-catalyzed decarboxylative cyclization of N-methacryloylbenzamides, providing a wide range of acylated isoquinolines derivatives [96]. A similar concept was applied for the formation of 2-acylindoles via a practical decarboxylative cyclization of 2-alkenylarylisocyanides with α-keto acids (Scheme 26a) [97]. Very recently, Prabhu et al. developed a decarboxylative acylation of electron-deficient heteroarenes in the presence of Na2S2O<sup>8</sup> (Scheme 26b) [98].

α

functionalization of α **Scheme 24.** (**a**) Radical decarboxylative functionalization of α-keto acids; (**b**) Decarboxylation coupling/ intramolecular cyclization sequence.

– **Scheme 25.** (**a**) Hypervalent iodine (BI–OAc)-mediated decarboxylative cyclization reaction; (**b**) Proposed mechanism.

α

alkenylarylisocyanides with α

α

–

**Scheme 26.** (**a**) Decarboxylative cyclization of 2-alkenylarylisocyanides with alkenylarylisocyanides with α α-keto acids; (**b**) Decarboxylative acylation of electron-deficient heteroarenes.

In addition, carbamoyl radicals are important radical species that have been widely used in cascade cyclization reactions for the construction of N-containing heterocycles [99]. In 2018, Feng et al. described an oxidative decarboxylation of oxamic acids to generate carbamoyl radical species (Scheme 27a) [100]. The carbamoyl radicals then react with electron-deficient alkenes for the synthesis of a range of 3,4-dihydroquinolin-2(1*H*)-ones.

**Scheme 27.** (**a**) Photocatalytic decarboxylative functionalization of oxamic acids; (**b**) Proposed mechanism.

A plausible catalytic cycle is proposed in Scheme 27b. The reaction starts with a single-electron oxidation of oxamic acid by photoexcited catalyst Ir III \*, delivering the key carbamoyl radical **96-A** and IrII species. Intermediate **96-A** reacts with an electron-deficient alkene **97** to give C-based radical **96-B**, which undergoes a rapid intramolecular cyclization to form radical **96-C**. At the same time, the Ir II catalyst can be oxidized by O<sup>2</sup> to regenerate the ground state of photocatalyst, along with the formation of oxygen radical anion. Finally, the H-atom abstraction from intermediate **96-C** by oxygen radical anion delivers 3,4-dihydroquinolin-2(1*H*)-one products.

C−C

β –

In addition, Donald, Taylor and co-workers discovered a reductive decarboxylation process for the construction of 3,4-dihydroquinolin-2(1*H*)-ones (Scheme 28) [101]. In this reaction, the bench-stable and readily prepared N-hydroxyphthalimido oxamides were used as the carbamoyl radical precursors. A wide range of electron-deficient alkenes were successful radical acceptors, such as methyl methacrylate, ethyl vinyl ketone and acrylonitrile. Gratifyingly, the current reaction can be further applied for the assembly of some spirocyclic lactone lactams, which provides an important entry to biologically important spirocycles.

**Scheme 28.** Reductive decarboxylation of N-hydroxyphthalimido oxamides.

C−C β – Recently, Wu et al. demonstrated a novel C−C bond activation strategy for the generation of acyl radicals for the first time (Scheme 29) [102]. Under mild photocatalytic conditions, the β-C–C bond fragment of oxime esters leads to a range of aryl acyl radicals in high efficiency. More strikingly, the relatively unstable aliphatic acyl radicals can be successfully formed under the same catalytic system. The newly generated acyl radicals can react with diverse Michael acceptors, such as acrylamides, amines and isonitrile to furnish the desired heterocycles and other linear carbonyl compounds in good yields. A proposed mechanism is depicted in Scheme 30. Under photocatalytic conditions, oxime ester undergoes a fast SET reduction and β-C–C bond homolysis to deliver acyl radical species **102-A** with the elimination of a CH3CN molecule. The selective addition of radical **102-A** to acrylamide results in a C-radical **103-A**, followed by an intramolecular cyclization/single-electron oxidative aromatization cascade to afford the final products and complete the photocatalytic cycle. β –

– **Scheme 29.** (**a**) Photocatalytic C–C bond activation of oxime esters; (**b**) Photocatalytic [2+2] dimerization reaction.

–

–

β –

**Scheme 30.** Proposed mechanism of C–C bond activation in oxime esters. –

Surprisingly, the unexpected cyclobutanes could be obtained as the major products via a sequential SET activation and energy transfer (ET) process by using styrenes as acyl radical acceptors in DMF (Scheme 29b). The in situ generated aryl enone **107** proved to be the key intermediate, which undergoes a photocatalytic [2+2] dimerization to give the *anti*-cyclobutane products.

#### **6. Conclusions**

Acyl radical-meditated carbonylation has been esteemed as a powerful tool for the efficient construction of a wide range of high-value oxygen and nitrogen heterocycles. Under mild visible light photocatalytic conditions, these reactive acyl radical species can be conveniently generated from diverse acyl radical precursors. Outstanding features of these carbonylative reactions include mild conditions, good functional group tolerance, broad scope and high degree of regioselectivity. Significantly, these reactions have a promising potential in the concise synthesis of biologically active heterocycles and late-stage modification of natural products.

While significant progress emerged in this field, some important challenges remain and need to be addressed in near future. The reaction of unstable aliphatic acyl radicals is largely unexplored due to the unavoidable decarbonylation process. In addition, the radical acceptors of acyl radicals are mainly limited to electron-deficient species. We believe that the development of dual catalytic systems and design of new substrate types may provide solutions to these problems.

**Author Contributions:** X.-Q.H.: writing—original draft preparation; Z.-K.L.: writing—review and editing; W.-J.X.: supervision. All authors have read and agree to the published version of the manuscript.

**Funding:** This research was funded by the National Natural Science Foundation of China (21901258 and 21772053).

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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