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Synthesis 2024; 56(18): 2886-2898
DOI: 10.1055/a-2302-5824
short review

Stepwise Carbene Transfer Reaction with Alkenes beyond Cyclopropanation

Minghan Yao
a   College of Chemistry and Environmental Science, Laboratory of Xinjiang Native Medicinal and Edible Plant Resources Chemistry, Kashi University, Kashi 844000, P. R. of China
b   School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. of China
,
Shanliang Dong
b   School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. of China
,
Abdulla Yusuf
a   College of Chemistry and Environmental Science, Laboratory of Xinjiang Native Medicinal and Edible Plant Resources Chemistry, Kashi University, Kashi 844000, P. R. of China
,
Xinfang Xu∗
b   School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. of China
› Author Affiliations

Support for this research from the National Natural Science Foundation of China (22371309), Guangdong Provincial Key R & D Programme (21202107201900002), The Key Laboratory Open Project of Xinjiang Uygur Autonomous Region (2021D04018) and The Key Laboratory Open Project of Xinjiang Native Medicinal and Edible Plant Resources Chemistry (KSUZDSYS202103) is greatly acknowledged.
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Abstract

Metal carbene transfer reactions have been well-established as an indispensable tool in modern organic synthesis, especially in the construction of C–C and C–X bonds with high efficiency and selectivity. Among these, stepwise carbene transfer reaction with alkenes beyond classical cyclopropanation reaction has been demonstrated as a practical method for the effective olefinic C–H/C–C bond functionalization. This review highlights the recent achievements in this area for the direct C–C bond formation involving metal carbene species with alkenes through a through stepwise reaction pathway. The content of this review is organized into three general categories according to the types of the reactions, including (i) direct nucleophilic addition of alkenes with metal carbene species, (ii) cross-coupling reaction via an alkenylic C–H bond activation and migration insertion sequence, and (iii) catalytic coupling reaction involving radical intermediate. Considering this rapidly evolving field, detailed reaction mechanism, current limitations, and future research directions are discussed.

1 Introduction

2 Nucleophilic Addition of Alkenes to Metal Carbene Species

2.1 Using Polarized Alkenes

2.2 Using Unactivated Alkenes

2.3 Cascade Reactions

3 Cross-Coupling Reaction Involving Metal Carbene Migratory Insertion Process

4 Coupling Reaction Involving Radical Intermediate

5 Conclusions and Perspectives


#

Key words

metal carbene - diazo compound - reactive intermediate - C–C bond formation - nonaromatic C(sp2)–H functionalization - alkene functionalization
1

Introduction

Carbon–carbon (C–C) bond formation reaction is fundamental in organic synthesis. Over the past two decades, transition-metal-catalyzed carbene transfer reactions have emerged as highly potent and atom-economic methods for the direct construction of C–C bond that exempts from using pre-functionalization of the starting materials.[1] In the past decades, a variety of versatile catalytic transformations of in situ generated metal carbene intermediates have been well documented for the construction of C–C bonds, including but not limited to C–H bond insertion,[2] cycloaddition with alkenes[3] and alkynes,[4] and cross-coupling reaction.[5] With these approaches, simple and readily available materials, such as alkanes, can be smoothly functionalized or converted into multi-functionalized molecules, through precise and predictable chemo- and stereoselective carbene transformations, enabling the creation of pharmaceuticals, agrochemicals, and various natural products.

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Minghan Yao was born in 2001 (Anhui, China). He received his B.S. degree from Sun Yat-Sen University in 2023. In the same year, he joined the group of Prof. Xinfang Xu to pursue his Ph.D. at Sun Yat-Sen University. His current research interests focus on asymmetric catalysis and carbene chemistry. Shanliang Dong was born in 1995 (Anhui, China). He received his M.Sc. degree in 2020 from Soochow University. He is currently pursuing his Ph.D. at Sun Yat-Sen University under the supervision of Prof. Xinfang Xu. His current research interests mainly focus on asymmetric catalytic metal carbene transformations. Prof. Xinfang Xu was born in 1981 (Zhejiang, China). He obtained his Ph.D. degree in organic chemistry from East China Normal University in 2010. Then he conducted postdoctoral study at the University of Maryland with Prof. Michael P. Doyle (2010–2014). In 2014, he started his independent career at Soochow University. Now he is working as a full professor at the School of Pharmaceutical Sciences, Sun Yat-sen University. His research interests include asymmetric catalysis, carbene chemistry, cascade reaction and multi-component reaction, and bioactivity-oriented heterocycle synthesis. Assoc. Prof. Abdulla Yusuf was born in 1986 (Xinjiang, China). He obtained his Ph.D. degree in organic chemistry from University of Chinese Academy of Sciences in 2019. At Kashi University, his research is focused on structural modification of natural products and assessing its biological activity. In 2022, he joined Prof. Xinfang Xu's team as a visiting scholar. Now his research interests are introducing the carbene chemistry to structural modification of natural products.

Alkene, which is a large industrial petrochemical, serves as a prevalent chemical feedstock for the assembly of diverse complex molecules. Thus, the development of new and efficient methods for the alkene functionalization remains a focal point for the synthetic chemists and has attached extensive investigation. Beyond the metal carbene cyclopropanation (Scheme [1], path a),[3] there are many different types of C–C bond formation pathways of metal carbene species with alkenes, which has attracted increasing attention in the last decade and further enriches the synthetic toolbox, prompting us to review the status of this field.

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Scheme 1 Catalytic C–C bond formation reaction patterns of metal carbene with alkene

To enhance clarity, this review has been divided into three sections by the categories of reaction mechanism, including (i) direct nucleophilic addition of alkenes to metal carbene species via the zwitterionic intermediate (Scheme [1], path b), (ii) cross-coupling reaction through an alkenylic C–H bond activation and migration insertion sequence (Scheme [1], path c), and (iii) catalytic coupling reaction involving radical intermediate (Scheme [1], path d). This review will summarize the advance in transition-metal-catalyzed carbene transformation with alkenes beyond traditional cyclopropanation reaction dated up to early 2024. Considering this rapidly evolving field, detailed reaction mechanism, current limitations, and future research directions are discussed.


# 2

Nucleophilic Addition of Alkenes to Metal Carbene Species

2.1

Using Polarized Alkenes

Generally, the metal carbene cyclopropanation reaction with alkene went through a concerted reaction pathway via a three-membered transition state. However, in the cases of reaction with polarizable alkenes, such as enol ethers, enaminones, enamines, or enamides, the stepwise mechanism leading to the alkenyl C(sp2)–H bond insertion products via a zwitterionic intermediate has also been disclosed. Due to the reactivity of polarized nucleophilic alkenes, the zwitterionic intermediate underwent a proton transfer with complete preference over the competitive cyclopropanation process to provide C(sp2)–H bond alkylation product. In 1985, Alonso first reported the reaction of diazomalonates 1 with enol ethers 2, affording the alkenyl C(sp2)–H bond insertion products 3.[6] In this seminal work, the key zwitterionic intermediate was proposed in this transformation through a nucleophilic addition process, although only two examples have been reported in low yields (Scheme [2]).

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Scheme 2 Copper-catalyzed carbene insertion into alkenyl C(sp2)–H bond of enol ether
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Scheme 3 Rh(II)-catalyzed alkenyl C(sp2)–H bond alkylation. a Performed with 1,2-DCE at 80 °C. b The reaction was performed with Rh2(OAc)4 in CHCl3 at 80 °C. c The reaction was conducted at 0 °C–RT.d The reaction was performed with CHCl3 upon heating at reflux.

Inspired by this work, Musaev and France devised a Rh(II)-catalyzed method for the alkenyl C(sp2)–H bond alkylation using diazo compounds 4 and polarized alkenes 5 (Scheme [3]).[7] This alkylation reaction tolerated a broad spectrum of α-diazo-1,3-dicarbonyl compounds, including α-diazomalonates, α-diazomalonamides, and β-keto esters, leading to the insertion products 6a–g in good to high yields. Additionally, both cyclic and acyclic polarized alkenes, including enol ethers, enamides, and enecarbamates are compatible substrates, and can be effectively transformed to the desired insertion products 6h,i. The alkylation reaction is proposed to proceed via an addition-elimination sequence. Nucleophilic addition of dihydrofuran to the rhodium carbene results in the zwitterionic intermediate Int-1. The negatively charged fragment of Int-1 is stabilized by the adjacent carbonyl group, while the positive charge is delocalized with the oxonium group. Then, elimination of the β-hydrogen from Int-1 yields the enol species Int-2, which tautomerizes to produce the β-alkylated product 6, while a competitive pathway that involves the attack of the carbonyl oxygen of the oxonium, could result in the formation of 2,3-dihydrofuran product 7 via a formal [3+2] cycloaddition, which is also described in other reports.[8]

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Scheme 4 Nucleophilic addition of enamines to the metal carbenes

To evaluate the factors that influence the reactivity of enol ethers (β-alkylation vs cycloaddition), the proposed addition-elimination mechanism has been investigated both experimentally and computationally. As seen in Scheme [3], at 40 °C, the formation of the cycloaddition product 7 predominates, observed in a 12:1 ratio compared to the β-alkylated product 6. Conversely, at 60 °C, the ratio shifts to 17:1 in favor of the β-alkylated product 6. Consistent with experimental findings, the DFT calculations also corroborate these observations. Based on these results, the reaction was proposed to proceed under thermodynamic control at higher temperatures. In addition to the acceptor-acceptor diazo compounds, diazo indolinones have also been reported to work well for the β-alkylation with enaminones, yielding the Heck-type functionalized β-alkylated enaminones.[9]

Due to the moisture sensitivity, the alkylated polarized alkenes could be hydrolyzed to furnish the keto esters instead. Yan’s group described a new reaction involving aryldiazoacetates 8 and enamines 9 with the Cu(hfacac)2 as the catalyst (Scheme [4]).[10] Initially formed β-alkylated enamine Int-5 was detected by 1H NMR and IR spectroscopy, but due to the moisture sensitivity, only the corresponding γ-keto esters 10 were isolated. A wide range of enamines derived from aryl alkyl ketones were compatible, providing γ-keto esters products 10a–f in good to excellent yields. β-Phenyl- or methyl-substituted enamines provided γ-keto esters 10e or 10f as diastereomeric mixtures in good yields. Unfortunately, enamines derived from dialkyl ketones and α,α-disubstituted aryl alkyl ketones were not suitable substrates (10j–l). All examined aryl- and heteroaryl-diazoacetates afforded γ-keto esters in good yields in this transformation. The proposed mechanism involves the nucleophilic addition of enamine to the metal carbene, yielding a metal-containing zwitterionic intermediate Int-3, which further transforms into Int-4 after demetalation. Then, Int-4 undergoes a proton transfer, rather than the competitive cyclopropanation process, to form the enamine species Int-5. Upon hydrolysis over silica gel, enamine Int-5 converts to γ-keto ester 10a as the final product. In addition to enamine, other types of elaborately designed polarized alkenes have also been known for the direct nucleophilic addition with metal carbene species to give the formal insertion products.[11]

Despite these significant advancements in the nucleophilic addition of polarized electron-rich alkenes with metal carbene, the asymmetric version in this area remains a challenge. Until 2017, Gong’s group devised an enantioselective aza-ene-type reaction of enamides with gold carbenes, which is enabled by asymmetric relay catalysis with a combination of a gold complex and a chiral phosphoric acid.[12] In the presence of XphosAuNTf2 (10 mol%) and CPA1 (0.1 mol%), the reaction between α-diazo esters 11 and enamides 12 provided the desired γ-keto esters 13 in moderate to good yields with excellent enantioselectivity. Various substituents on the aromatic ring of the α-diazo esters 11 and enamides 12 are tolerated, and the reaction delivered the desired alkylated products 13a–I in high yields with acceptable enantioselectivity. Unfortunately, the reaction with an alkyl-substituted enamide afforded the corresponding alkylated products 13e in 62% yield and 42% ee under the standard condition. A plausible mechanism has been proposed based on the isotope labeling experiments and theoretical studies. The reaction proceeds through the nucleophilic addition of enamide 12 with gold carbene species to afford the gold-associated intermediate Int-6. Subsequently, the intermediate Int-6 undergoes a proton transfer, leading to the formation of a thermodynamically stable enol species Int-7 via Int-6′. With the assistance of chiral phosphoric acid CPA1, the enol Int-7 undergoes an asymmetric protonation process to furnish the moisture-sensitive imine, which is transformed into γ-keto esters 13 smoothly during the isolation in excellent yields and enantioselectivities (Scheme [5]).

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Scheme 5 Enantioselective aza-ene-type reaction of enamides with gold carbenes

# 2.2

Using Unactivated Alkenes

In the cases of metal carbene alkenyl C(sp2)–H bond insertion with unactivated alkenes, it often encounters the issues such as poor reactivity, and side reactions including cyclopropanation,[3] allyl C(sp3)–H bonds insertion reaction,[13] and others.[14] To achieve highly efficient and chemoselective nucleophilic addition of unactivated alkenes to metal carbene species, diverse catalytic strategies related to different types of substrates have been developed.

In 2017, Wang’s group developed an elegant methodology for the rhodium(II)- or copper(I)-catalyzed formal intramolecular carbene insertion into alkenyl C(sp2)–H bond.[15] In the presence of Rh2(Oct)4 (0.5 mol%) or CuI (10 mol%) as the catalyst, and LiOtBu (1.05 equiv) as the base in toluene, the reaction provided the desired formal alkenyl C(sp2)–H bond insertion products 1H-indenes 15 and 15′ in moderate to good yields. Prolonging of the reaction time resulted in an increased ratio of 15e′ to 15e with little impact on the yield, implying a potential slow transformation of 15′ into 15 under these reaction conditions. Various substituents on the aromatic ring of the N-tosylhydrazones 14 and the alkenes are tolerated. The authors proposed a stepwise mechanism involving a metal carbene formation, nucleophilic addition, dearomatization, and rearomatization sequence (Scheme [6]).

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Scheme 6 Formal intramolecular carbene insertion of alkenyl C(sp2)–H bonds with N-tosylhydrazones as carbene precursors. a Results in parentheses are under CuI catalysis.

In addition to tosylhydrazones, alkynes could also be used as carbene precursors for the addition with alkenes. Liu’s group disclosed the first intramolecular cyclization of α-carbonyl gold(I) carbene species with a tethered alkene moiety to afford 3-carbonyl-1H-indene compounds 17 in excellent yields (Scheme [7]).[16] In the presence of 1.2 equivalents of 8-methylquinoline N-oxide and 5 mol% JohnPhosAuCl/AgNTf2 catalyst at 25 °C, 1,5-enynes 16 were smoothly converted to the target products 17. The 1,5-enynes with diverse amino groups yield 3-carbonyl-1H-indene products 17a–g efficiently (78–95%). This transformation also works well with 1,5-enynes bearing a chloro or methoxy substituents at the phenyl C4 and C5 carbon atoms, forming the desired 17h–k in 55–85% yields. Additionally, the reaction involving 1,2-disubstituted alkene (E/Z = 2.4:1) proceeds to yield the product 17l in 49% yield.

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Scheme 7 Oxidative cyclization of 1,5-enynes via nucleophilic addition of alkene with in situ formed gold(I) carbene species

Based on the isotope labeling experiments, a reaction mechanism is proposed as shown in Scheme [7]. Initially, the 1,5-enyne is converted to α-carbonyl gold(I) carbene intermediate Int-9 via Int-8 with 8-methylquinoline N-oxide as oxidant in the presence of gold catalyst. Then, nucleophilic attack by the π-elections of the tethered alkene unit generates the gold containing benzyl cation Int-10. Subsequently, a 1,2-H shift leads to the formal insertion products.

By using in situ generated reactive gold carbene intermediates via gold-catalyzed retro-Büchner reaction, Echavarren­ reported an intramolecular formal alkenylic C–H bond insertion reaction for the synthesis of indenes. With the cationic gold(I) complex JohnPhosAuSbF6 as the catalyst, (E)-7-(2-styrylphenyl)cyclohepta-1,3,5-trienes 18 were transformed into 2-phenyl-1H-indenes 19.[17] This reaction exhibits broad compatibility with substrates bearing alkyl, alkenyl, or aryl substituents to give indenes 19a–h in moderate to good yields. However, the reaction with substrates 18i–k bearing substitution on the linkage benzene led to a mixture of indenes 19 and 19′. The control reaction with 18a-d 1 under standard conditions was conducted, which resulted exclusively in the formation of 19a-d 1 with the deuterium label at the methylene position. This observation contradicts an isomerization pathway via [1,5]-H sigmatropic migrations, which would have also produced 19a′-d 1 , indicating a different mechanism insight for the formation of these two isomers. A further mechanistic inspection was conducted by density functional theory (DFT) calculations. Following the retro-Büchner reaction, the highly electrophilic gold(I) carbene undergoes addition with the tethered alkene, resulting in the formation of benzylic carbocation Int-11. This intermediate Int-11 can proceed via a direct 1,2-H shift to form the (η2-indene) gold(I) complex (Scheme [8], path a) or undergo an unprecedented suprafacial 1,4-metallotropic migration pathway (Scheme [8], path b), followed by demetalation to give the formal insertion products 19 and 19′, respectively.

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Scheme 8Nucleophilic addition of alkene to the gold(I) carbenes generated from retro-Büchner reaction

Conjugated enynones have been known for the generation of donor-donor metal carbene species.[18] In 2018, Xu reported a formal intramolecular carbene insertion into alkenyl C(sp2)–H bond, which was facilitated by the donor-donor type copper carbene species generated from conjugated enynones.[19] The reaction proceeded via a copper-catalyzed 5-exo-dig cyclization of enynones to afford the copper (2-furyl)carbene intermediate, which then undergoes formal C(sp2)–H insertion to provide the furyl-substituted 1H-indenes 21. The DFT calculations suggest that the proposed formal C(sp2)–H insertion is a stepwise process, involving the initial nucleophilic addition with π-bond to give the dearomatized intermediate, followed by a 1,5-H shift (Scheme [9]). This approach offered an efficient method using environmentally friendly copper catalysts, with mild and neutral reaction conditions, broad functional-group compatibility, and high atom economy. Other types of carbene precursors with corresponding metal catalysts have also been documented to engage in the analogous intramolecular nucleophilic addition process with unactivated alkenes,[20] which further enriched the synthetic toolbox for constructing diverse cyclic structures from readily available alkenes.

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Scheme 9 Formal intramolecular carbene insertion into alkenyl C(sp2)–H bond using conjugated enynones as carbene precursors

The intermolecular metal carbene insertion reaction with simple and readily available alkenes presents more challenging due to the competitive cyclopropanation reaction. By taking advantages of gold(I) catalyst, López reported a chemoselective gold(I)-catalyzed coupling reaction of alkene and vinyldiazo compounds in CH2Cl2 at room temperature, giving the functionalized alkenes in moderate yields.[21] The proposed mechanism involves an initial formation of a gold carbene intermediate Int-12 from the diazo compound with the gold catalyst, which can be described as an allyl gold cation intermediate Int-12′. Subsequently, regioselective nucleophilic addition of the alkene substrate at the C3 position of the allyl cation generates the carbocation intermediate Int-13. Followed by deprotonation and demetalation completes the reaction to give the formal insertion products 24 and regenerate the catalyst (Scheme [10]).

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Scheme 10 Gold(I) catalyzed intermolecular C–C bonds formation of unactivated alkenes with vinyl diazo compounds

Recently, Zhou’s group reported a chemoselective formal intermolecular carbene insertion into alkenyl C(sp2)–H bond, wherein gold(I) catalyst proved to be more efficient than the other screened metal catalysts.[22] Under gold(I) catalysis, C4-alkenyl isochromanones 27 and isoquinolinones 28 were obtained from corresponding diazo reagents 25 and α-methylstyrenes 26 in moderate to good yields and excellent chemoselectivity. This method tolerates various α-methylstyrenes 26 and cyclic diazo compounds 25 with different ring sizes (Scheme [11]). The authors proposed two possible pathways: 1) nucleophilic attack-selective elimination process (Scheme [11], path a); 2) cyclopropanation-ring opening-olefin isomerization sequence (Scheme [11], path b). For path a, the gold carbene acted as a gold-stabilized carbocation and was attacked by the nucleophilic α-methylstyrenes, leading to the carbocation intermediate. Then, followed by elimination and demetalation sequence to give the formal alkenyl C(sp3)–H bond insertion products 28a. For path b, the gold carbene intermediate underwent a cyclopropanation reaction with α-methylstyrene 26a to afford cyclopropane, followed by a ring opening reaction that was facilitated by the in situ formed Brønsted acid, TfOH though the hydrolysis of Ph3PAuOTf. Subsequently, intramolecular proton transfer of the enol intermediate delivered the desired formal vinylic C(sp2)–H insertion product 27a. Moreover, the formal allylic C(sp3)–H insertion product could convert to thermodynamically stable 27 effectively via the olefin isomerization process. Utilizing the distinct reactivity of gold(I) carbenes, stepwise intermolecular alkenyl C–H functionalization and cycloaddition have also been achieved with cyclopentadienes and diazo compounds as carbene precursors.[23]

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Scheme 11 Gold(I)-catalyzed intermolecular formal carbene insertion into alkenyl C(sp2)–H bond and allylic C(sp3)–H bond

# 2.3

Cascade Reactions

Over the past two decades, both polarized alkenes and unactivated alkenes have been served as nucleophiles for the addition with metal carbenes, which generate the zwitterionic intermediate that features as a 1,3-dipole. In recent years, cascade reaction involving interception of these in situ generated all-carbon zwitterionic intermediates has also attracted much attention. This direction further expanded the scope of metal carbene mediated [3+2]-cycloaddition using zwitterionic intermediate as a 1,3-dipole, instead of azomethine imines ylides (from imine) and carbonyl ylide (from carbonyl compounds).

In 2020, Ye reported a copper-catalyzed asymmetric formal [3+2]-cycloaddition of all-carbon 1,3-dipoles generated from copper carbene species with tethered alkenes. This protocol offers a practical and atom-economical approach towards sp3-rich chiral pyrrole-fused bridged [2.2.1]-skeletons 31, featuring two all-carbon quaternary stereocenters, with excellent chemo-, diastereo-, and enantioselectivity (up to 90% yield, dr >50/1, up to >99% ee).[24] The reaction tolerated a variety of functionalized ynamides 29 and styrenes 30. A plausible mechanism based on control experimental results has been proposed: (i) generation of copper carbene intermediate Int-14 from the alkenyl N-propargylynamides 29 under copper catalysis, (ii) intramolecular nucleophilic addition with tethered alkene to afford a Cu-containing 1,3-dipole intermediate Int-15, and (iii) interception of the 1,3-dipole intermediate Int-15 by external alkenes 30 though a formal [3+2] cycloaddition led to the desired products 31 and regeneration of the copper catalyst (Scheme [12]).

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Scheme 12 Copper(I)-catalyzed formal [3+2]-cycloaddition using 1,3-dipole derived from nucleophilic addition of alkenes with copper carbene species. a 10 equiv amount of styrene was used. b At 40 °C.

Thereafter, Xu disclosed a gold(I)-catalyzed stepwise [4+2]-cycloaddition reaction of in situ formed carbene intermediate with alkenes.[25] A variety of polycarbocyclic frameworks 34 are obtained in good to excellent yields. These generated products could be readily converted to elusive π-conjugated polycyclic hydrocarbons (CPHs) with multiple substituents under a mild oxidation procedure. Based on experimental results and reported literature, a plausible mechanism is proposed (Scheme [13]). Initially, a 6-endo-dig carbocyclization of 32 promoted by gold(I) complex, results in an alkenyl-gold intermediate Int-16, which is further transformed into the key vinyl gold-carbene species Int-17 with simultaneous extrusion of a molecule of N2. Subsequently, the external alkenes 33 (serving as 2-C synthon) undergo a nucleophilic addition with this carbene intermediate, which features a carbocation-like reactivity and serves as a 4-C synthon, forming the carbocation intermediate Int-18. An intramolecular Friedel–Crafts-type cyclization results in the formation of the polycyclic products 34 and regenerates the gold(I) catalyst. Notably, the carbocation species Int-18 could also be trapped by external nucleophilic alcohols, which further confirmed the stepwise reaction mechanism of gold carbene addition with alkene.

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Scheme 13Gold(I)-catalyzed stepwise [4+2]-cycloaddition reaction of gold carbene intermediates with alkenes

Very recently, the same group has achieved a novel and efficient enantioselective three-component reaction of α-diazoketones 36 with alkenes 35 and 1,3,5-triazines 37 under dirhodium/chiral phosphoric acid cooperative catalysis.[26] Different substitutions on the 1,3,5-triazines and diazoketones work very well (38a–h), and a variety of exocyclic terminal alkenes are also well tolerated as the nucleophiles (38l–o) in this reaction. This approach features an unprecedented gem-dialkylation process, enabling an atom-economic synthesis of poly-functionalized chiral ketones in high yields and excellent enantioselectivities. The proposed reaction mechanism involves the initial decomposition of diazoketones 36, forming a highly electrophilic rhodium carbene species, followed by an intermolecular nucleophilic addition with alkenes to generate the key cationic intermediates Int-19. By means of the well-designed exocyclic alkene structure, the key cationic intermediates Int-19 could be stabilized though a π–π conjugation with the adjacent hetero atom or aryl group. Subsequent intramolecular proton transfer leads to the formation of a more thermodynamically stable enol species Int-20, which is detected by 1H NMR analysis. Finally, the enol species undergo an asymmetric Mannich-type addition process with external electrophiles with the assistance of chiral phosphoric acid, affording chiral ketone products 38 with high to excellent ee (Scheme [14]).

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Scheme 14Enantioselective three-component reaction of a-diazo ketones with alkenes and 1,3,5-triazines. a At 0 °C.

The reaction pattern of allenes and metal carbenes is rare and remains an underexplored area. In 2017, Echavarren reported a formal [3+2]-cycloaddition of terminal allenes 41 with aryl or styryl gold(I) carbenes generated by a retro-Büchner reaction.[27] Indenes and cyclopentadienes are obtained in acceptable yields (Scheme [15]). Notably, these cycloaddition products have been applied to the construction of the key carbon skeleton of several natural products (43b). Mechanistically, the reaction is proposed to involve the following sequence: initially, metal carbene is formed by retro-Büchner reaction, followed by intermolecular nucleophilic addition of allenes 41 with electron-deficient gold(I) carbene to give an allyl cationic species Int-21. Subsequently, intramolecular cyclization and isomerization furnished the cyclic product 42 or 43 and regenerated the gold catalyst.

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Scheme 15 Gold(I)-catalyzed formal [3+2] cycloaddition using cyclopentadienes as carbene precursors

#
# 3

Cross-Coupling Reaction Involving Metal Carbene Migratory Insertion Process

Transition-metal-catalyzed cross-coupling reaction involving a carbene migratory insertion process offered a potent and atom-economic method for the direct construction of C–C bond.[5] Different from the direct nucleophilic addition to metal carbene species of divergent nucleophiles, this reaction is initiated with the generation of organometallic species, followed by the generation of metal carbene intermediate and a migration insertion process. Generally, directing groups play a crucial role this area. Using azoles as directing group, Ellman described a Rh(III)-catalyzed method for alkenyl C(sp2)–H functionalization via metal carbene migratory insertion process.[28] With the [Cp*RhCl2]2 as the catalyst, AgSbF6 as the additive, alkenyl azoles 44 reacted with the diazo ketones 45 in tetrahydrofuran, providing the pyridine derivatives 46 in good to excellent yields. This methodology offers an efficient access to a diverse imidazopyridines and triazolopyridines 46a–d incorporating various substituents. Either acceptor/acceptor or donor/acceptor diazo compounds are tolerated (46e–f). The directing group 2-pyridyl plays a crucial role in enabling the initial alkenyl C(sp2)–H bond metalation and deprotonation process. Sequentially, metal-carbene formation, migratory insertion, protonolysis, and cyclization furnished the final adducts (Scheme [16]). Using pyrazole or indazole as the directing groups, Lee also developed a variant cycloaddition, providing the corresponding furan derivatives in good to excellent yields.[29]

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Scheme 16 Rh(III)-catalyzed alkenyl C(sp2)–H functionalization via carbene migratory insertion process

Dai described a Rh(III)-catalyzed domino annulation of diazo-oxindoles 48 with olefins 47 using tethered amide unit as the directing group, to give the spirooxindole pyrrolone products 49 in good yields and with excellent regioselectivities.[30] With 2.5 mol% of [Cp*RhCl2]2 as catalyst, acetonitrile as solvent, the reaction of N-pivaloyloxymethacrylamides 47 with diazo-oxindoles demonstrated robust reactivity. A diverse array of α-substituted N-pivaloyloxy acrylamides (49a–d) and N- or arene-substituted diazo-oxindoles (49e–i) exhibited good tolerance. Alkenes with steric hindrance did not have an adverse effect on the yields (49b,c). Based on control experiment, the proposed mechanism suggests that the alkenyl C–H bond cleavage is promoted by [RhCp*Cl2]2 as aforementioned transformation. Five-membered rhodacycle species Int-22 is considered as the reactive intermediate to enable the carbene migratory insertion process with the diazo compounds, leading to a new alkyl rhodium species Int-23, which undergoes a formal Lossen rearrangement to generate isocyanates. Subsequently, intramolecular nucleophilic attack of the alkyl rhodium species to the isocyanate moiety furnishes the spiro products 49 (Scheme [17]).

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Scheme 17Rh(III)-catalyzed alkenyl C(sp2)–H activation/carbene migratory insertion/Lossen rearrangement cascade reaction

Beyond the diazo compounds, other carbene precursors are also known for the Rh(III)-catalyzed intermolecular alkenyl C–H functionalization via carbene migratory insertion reaction. With [Cp*RhCl2]2 as catalyst, NaOAc as addictive, HFIP as solvent, simple acrylic acids 50 reacted with iodonium ylides 51 to give lactone products 52.[31] Acrylic acids with alkyl or aryl groups could be well tolerated to give the lactone products 52a–c in good to excellent yields. Cyclic acrylic acids exhibited lower efficiency (51d,e, in 20–30% yields). Unfortunately, no corresponding product was detected from simple acrylic acid and β-ethylacrylic acid. For iodonium ylides, a variety of substituted cyclohexane-1,3-diones provided the desired products 52f–h in good to excellent yields, but all the tested acyclic iodonium ylides all failed to undergo the coupling reaction under the standard conditions. A Rh(III)-catalyzed alkenyl C–H activation/carbene migratory insertion/cyclization sequence was proposed for the reaction outcomes based on control experiments and reported literature (Scheme [16] and 17). The rhodium carbene complex Int-24 is considered as the key reactive intermediate in this reaction (Scheme [18]).

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Scheme 18 Rh(III)-catalyzed alkenyl C(sp2)–H functionalization using iodonium ylides as carbene precursors

# 4

Coupling Reaction Involving Radical Intermediate

As a variation of metal carbene species, the metalloradical intermediate, featuring a single electron in the carbon-centered SOMO, exhibits distinct radical-type stepwise reactivity as opposed to the conventional concerted reaction pathway of Fischer-type carbenes.[32] Specifically, cobalt complexes have shown to be highly suitable for the stepwise metalloradical transfer reaction with unsaturated alkenyl C=C π-bond.[33]

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Scheme 19 Cobalt(I)-catalyzed alkenyl C(sp2)–H alkylation of terminal olefins with diazo reagents

In addition to the well-documented stepwise cyclopropanation reaction involving the carbene radical species, an alkenyl C(sp2)–H bond alkylation of electron-rich alkenes with diazo compounds was reported by Gryko in 2014.[34] Ethyl diazoacetate (EDA, 54) reacted with alkenes 53 in the presence of Cble(III), a natural nontoxic vitamin B12 derivative, and a reducing system (Zn/NH4Cl) under light irradiation (Scheme [19]). In this reaction, a mixture of two compounds formed: unsaturated Heck-type products 55 and saturated ester 56 with the double bond reduced. Thus, the subsequent hydrogenation was performed to exclusively furnish the saturated product 56. The developed methodology could be extended beyond electron-rich olefins, enabling the functionalization of enol ethers 55a, enamides 55b, and vinyl sulfides (56e) smoothly. Notably, in all tested cases, cyclopropanation was not observed.

Based on experimental findings, a plausible mechanism was proposed. First, the Cble(III) is reduced to the catalytically active cobalt(I) form, which subsequently interacts with EDA to form alkyl-cobalester(III) species Int-25. Next, homolytic bond cleavage of the alkyl-cobalester(III) species Int-25 leads to radical intermediate Int-26 by heating or light irradiation. The key C–C bond-formation step involves the radical addition of Int-26 to the electron-rich olefin to form another radical Int-27. Then, radical Int-27 can either recombine with cobalt(II) species to give the intermediate Int-28, or disproportionate leading to saturated product 56. Finally, intermediate Int-28 undergoes dehydrocobaltation to form the desired product 55 and hydridocobalester [Co(III)–H] that upon reduction regenerates the catalyst or reacts with olefin 55 to produce the reduced product 56.

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Scheme 20Cobalt(II)-catalyzed intramolecular C(sp2)–H insertion for the synthesis of substituted 1H‑indenes

Apart from the radical addition to electron-rich unsaturated π-bond, addition to the electron-deficient C=C π-bond of cobalt(III) carbene radical is another important pathway. The cheap and readily available cobalt(II) complex, [Co(MeTAA)] (MeTAA = tetramethyltetraaza[14]annulene), has proved to be the most active catalyst to enable the intramolecular carbene insertion of alkenyl C–H bond (Scheme [20]).[35] The methodology has been successfully applied to a broad range of substrates, producing functionalized 1H-indenes 58 in good to excellent yields. Using o-cinnamyl N-tosylhydrazones 57 as carbene precursors, a series of electron-withdrawing groups as well as phenyl on the vinylic double bond was well tolerated (58a–d). The substituents on the aromatic ring had little impact on the reactivity. Notably, the unsymmetrical substrates usually lead to a mixture of two regioisomeric products 58e and 58e′, indicating allylic/benzylic double bond isomerization under the current conditions, which is also supported by deuterium labeling experiments. Based on DFT studies and supporting radical-scavenging experiments, the proposed mechanism suggests that the diazo compound is activated resulting in the formation of a Co(III)-carbene radical Int-29. Subsequently, rate limiting radical ring-closure step produces an indanyl-radical intermediate Int-30, followed by a 1,2-hydrogen atom transfer, leading to the 1H-indene products 58 and regenerating the Co(II) catalyst.


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Conclusions and Perspectives

As summarized in this review, the field of stepwise carbene transfer reactions with alkenes beyond the cyclopropanation have been properly developed in the past decade. In this short review, we have summarized recent progress by divided into three segments from the different mechanism. In the first part, alkenes undergo a direct nucleophilic addition with metal carbene species. Both polarized and unactuated alkenes are capable in this method with different metal carbene precursors and catalytic systems, especially with the gold(I) carbene intermediates. Moreover, the cascade reaction through the interception of the in situ generated zwitterionic intermediates provides a highly efficient and atom-economic access to assembly complex architectures from readily available substrates. In the second reaction pattern, various directing groups are applied for the initial alkenyl C(sp2)–H bonds activation by metal catalysis, followed by metal carbene migration insertion process, and generally leading to the cyclic frameworks. In the third section, a distinct cobalt catalyst offered a radical-type reaction pattern with alkenes, directly forming the coupling products. In this area, the regio- and stereoselectivity control remains a challenge, for example, the location of the newly formed π-bond is volatile in some cases, and the Z/E selectivity and enantioselectivity generally relied on the substrate, instead of by the catalyst, although there are a few of asymmetric catalytic versions have been disclosed.

For the future work, additional insight will be gained through development of new catalyst-control strategies for the stepwise carbene transfer with simple and readily available alkenes. Considering the unique property of gold(I) and cobalt(III) carbenes (or metalloradical species), exploration the novel reactivity of these intermediates with structural diversity should be the direction to control the selectivity in this area. Importantly, employing these in situ generated cation intermediates that derived from metal carbene addition with π-bond in cascade reaction presents as a prospective approach to constructing multiple C–C bonds in one reaction, although it is still at the initial stage of the development. Broad applications could be envisioned for the synthesis of complex architectures and highly valuable molecules with this stepwise carbene transfer strategy, which could be served as one of the robust methods in toolbox for the direct construction of C–C bond.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Xinfang Xu
School of Pharmaceutical Sciences, Sun Yat-sen University
Guangzhou 510006
P. R. of China   

Publication History

Received: 13 March 2024

Accepted after revision: 09 April 2024

Accepted Manuscript online:
09 April 2024

Article published online:
17 April 2024

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Minghan Yao was born in 2001 (Anhui, China). He received his B.S. degree from Sun Yat-Sen University in 2023. In the same year, he joined the group of Prof. Xinfang Xu to pursue his Ph.D. at Sun Yat-Sen University. His current research interests focus on asymmetric catalysis and carbene chemistry. Shanliang Dong was born in 1995 (Anhui, China). He received his M.Sc. degree in 2020 from Soochow University. He is currently pursuing his Ph.D. at Sun Yat-Sen University under the supervision of Prof. Xinfang Xu. His current research interests mainly focus on asymmetric catalytic metal carbene transformations. Prof. Xinfang Xu was born in 1981 (Zhejiang, China). He obtained his Ph.D. degree in organic chemistry from East China Normal University in 2010. Then he conducted postdoctoral study at the University of Maryland with Prof. Michael P. Doyle (2010–2014). In 2014, he started his independent career at Soochow University. Now he is working as a full professor at the School of Pharmaceutical Sciences, Sun Yat-sen University. His research interests include asymmetric catalysis, carbene chemistry, cascade reaction and multi-component reaction, and bioactivity-oriented heterocycle synthesis. Assoc. Prof. Abdulla Yusuf was born in 1986 (Xinjiang, China). He obtained his Ph.D. degree in organic chemistry from University of Chinese Academy of Sciences in 2019. At Kashi University, his research is focused on structural modification of natural products and assessing its biological activity. In 2022, he joined Prof. Xinfang Xu's team as a visiting scholar. Now his research interests are introducing the carbene chemistry to structural modification of natural products.
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Scheme 1 Catalytic C–C bond formation reaction patterns of metal carbene with alkene
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Scheme 2 Copper-catalyzed carbene insertion into alkenyl C(sp2)–H bond of enol ether
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Scheme 3 Rh(II)-catalyzed alkenyl C(sp2)–H bond alkylation. a Performed with 1,2-DCE at 80 °C. b The reaction was performed with Rh2(OAc)4 in CHCl3 at 80 °C. c The reaction was conducted at 0 °C–RT.d The reaction was performed with CHCl3 upon heating at reflux.
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Scheme 4 Nucleophilic addition of enamines to the metal carbenes
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Scheme 5 Enantioselective aza-ene-type reaction of enamides with gold carbenes
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Scheme 6 Formal intramolecular carbene insertion of alkenyl C(sp2)–H bonds with N-tosylhydrazones as carbene precursors. a Results in parentheses are under CuI catalysis.
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Scheme 7 Oxidative cyclization of 1,5-enynes via nucleophilic addition of alkene with in situ formed gold(I) carbene species
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Scheme 8Nucleophilic addition of alkene to the gold(I) carbenes generated from retro-Büchner reaction
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Scheme 9 Formal intramolecular carbene insertion into alkenyl C(sp2)–H bond using conjugated enynones as carbene precursors
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Scheme 10 Gold(I) catalyzed intermolecular C–C bonds formation of unactivated alkenes with vinyl diazo compounds
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Scheme 11 Gold(I)-catalyzed intermolecular formal carbene insertion into alkenyl C(sp2)–H bond and allylic C(sp3)–H bond
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Scheme 12 Copper(I)-catalyzed formal [3+2]-cycloaddition using 1,3-dipole derived from nucleophilic addition of alkenes with copper carbene species. a 10 equiv amount of styrene was used. b At 40 °C.
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Scheme 13Gold(I)-catalyzed stepwise [4+2]-cycloaddition reaction of gold carbene intermediates with alkenes
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Scheme 14Enantioselective three-component reaction of a-diazo ketones with alkenes and 1,3,5-triazines. a At 0 °C.
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Scheme 15 Gold(I)-catalyzed formal [3+2] cycloaddition using cyclopentadienes as carbene precursors
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Scheme 16 Rh(III)-catalyzed alkenyl C(sp2)–H functionalization via carbene migratory insertion process
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Scheme 17Rh(III)-catalyzed alkenyl C(sp2)–H activation/carbene migratory insertion/Lossen rearrangement cascade reaction
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Scheme 18 Rh(III)-catalyzed alkenyl C(sp2)–H functionalization using iodonium ylides as carbene precursors
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Scheme 19 Cobalt(I)-catalyzed alkenyl C(sp2)–H alkylation of terminal olefins with diazo reagents
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Scheme 20Cobalt(II)-catalyzed intramolecular C(sp2)–H insertion for the synthesis of substituted 1H‑indenes