Recent Advances in Catalytic Alkyne Transformation via Copper Carbene Intermediates

As one of the abundant and inexpensive metals on the earth, copper has demonstrated broad applications in synthetic chemistry and catalysis. Among these copper-catalyzed advances, copper carbenes are versatile and reactive intermediates that can mediate a variety of transformations, which have attracted much attention in the past decades. The present review summarizes two different reaction models that take place between a copper carbene intermediate and alkyne species, including the cross-coupling reaction of copper carbene intermediate with terminal alkyne, and the addition of copper carbene intermediate onto the C–C triple bond. This article will cover the profile from 2010 to 2021 by placing emphasis on the detailed catalytic models and highlighting the synthetic applications offered by these practical and mild methods.


Introduction
Transition-metal-catalyzed transformations of carbon-carbon triple bond have been presented as one of the most effective and prominent tools for the construction of functionalized molecules and fine chemicals [1][2][3][4]. Alkynes have low C sp -H pKa (~25), and the carbon-carbon triple bond could be selectively activated by π-acidic transition metals. These unique characteristics have rendered nucleophilic and/or electrophilic properties of alkynes, which make them versatile building blocks in the synthesis of natural products and biologically active molecules [5,6]. In this area, only a few metal complexes based on late transition metals such as platinum and coinage metals could enable the activation of alkynes [7][8][9].

Cross-Coupling Reaction of Copper Carbene Intermediate with Terminal Alkyne
Copper-catalyzed cross-coupling reaction of a copper carbene intermediate with terminal alkynes was one of the most powerful protocols for the construction of C-C bonds [87]. However, in early works, a mixture of alkynoates and allenoates was generated in combined moderate yields under harsh reaction conditions [88]. Until 2004, Fu reported the first example of the copper-catalyzed coupling reaction of terminal alkynes with diazo esters or diazo amides to yield 3-alkynoate or 3-butynamide products selectively with minimal amount of allene byproducts under no-basic conditions [89]. Consequently, a variety of copper-catalyzed coupling reactions of terminal alkynes with various carbene precursors have been developed independently.

Alkynylation Terminated by Protonation
In 2012, Wang reported a copper-catalyzed cross-coupling of N-tosylhydrazones 1 with trialkylsilylethynes 2, leading to the alkynylated products 4 via the formation of C(sp)-C(sp 3 ) bonds (Scheme 2). Mechanism study shows that migratory insertion of copper carbene species gives the alkynoate copper intermediate 3, and sequential protonation affords the target products 4. This coupling reaction proceeded efficiently with N-tosylhydrazones derived from aromatic and aliphatic aldehydes or ketones in moderate to excellent yields without detecting the formation of allene byproducts 5. However, when a tert-butyl substituted alkyne 7 was employed, the corresponding allene product 8 was formed selectively [90]. Later in 2014, Zhou reported a copper-catalyzed coupling reaction using dialkoxycarbenes 9 as carbene precursor [91], which provides unsymmetrical propargylic acetals 11 in moderate to good yields (Scheme 3). In 2018, an asymmetric coupling reaction of N-tosylhydrazones 12 with terminal alkynes 13 was achieved by Uozumi and co-workers using chiral copper(I)/phosphoramidite complex as the chiral catalyst (Scheme 4), and optically active alkynylated product 14 was generated in moderate to good yields and enantioselectivities [92].

Alkynylation Terminated by Electrophilic Addition
Beyond the copper-catalyzed alkynylation terminated by protonation, the alkynoate copper intermediates, formed in situ from copper carbene species and terminal alkynes, could be intercepted through a nucleophilic substitution or electrophilic addition process. In 2015, Wang and co-workers contributed a three-component cross-coupling reaction of terminal alkyne with α-diazo ester and alkyl halide or Michael acceptor [93]. In this transformation, α-diazoesters 15 react firstly with the (triisopropylsilyl)acetylene 16 through a migratory insertion process to form the alkynoate copper intermediate 17, followed by a nucleophilic substitution with alkyl halides 18 or Michael addition with electron-deficient alkenes 20 to produce the three-component products 19 and 21, respectively (Scheme 5). This transformation represents a highly efficient method for the construction of alkynylation products with an all-carbon quaternary center in moderate to high yields. Notably, the copper catalyst works as the only catalyst to install two new C-C bonds on the carbenic carbon in this reaction.  [94]. With this method, a series of trifluoromethyl-substituted dihydroisoxazoles 26 were obtained in high yields under mild conditions. Mechanistically, electrophilic trapping of the alkynoate copper intermediate by nitrosobenzenes was proposed as the key step in this cascade transformation, which forms a proposed intermediate 25, followed by a copper catalyzed intramolecular annulation to deliver the target products 26 (Scheme 6). One year later, the same group reported a copper-catalyzed three-component reaction of terminal alkynes 10 with α-diazoamides 27 and isatin ketimines 28 in 2019 [95]. A series of alkynyl-containing 3,3-disubstituted oxindoles 30 were efficiently formed in high yields and diastereoselectivities through a Mannich type trapping of an in situ generated alkynoate copper intermediate 29 (Scheme 7).

Alkynylation Terminated by β-Elimination
Besides the intermolecular trapping reactions of the alkynoate copper intermediate, β-H elimination could occur with this reactive species, providing a variety of conjugated enynes. Representative advances in this area have been reported by Wang's group [96][97][98]. In 2015, they reported a copper-catalyzed cross-coupling reaction of terminal alkynes 9 with trifluoromethyl ketone N-tosylhydrazones 31, which provides an efficient synthesis of 1,1-difluoro-1,3-enyne derivatives 33 under mild reaction conditions [96]. Mechanistically, the alkynoate copper intermediate 32 was generated in situ through a migratory insertion of the copper carbene intermediate, followed by β-F elimination, leading to the gem-difluoroolefination products 33 in moderate to high yields [Scheme 8, Eq. (a)]. Later, the author reported a copper-catalyzed three-component reaction of a (triisopropylsilyl)acetylene 16 with Ethyl diazoacetate 34 (EDA) and aldehydes 35 that provided an efficient method for the synthesis of α-alkynyl-α, β-unsaturated esters 37 [97]. In this cascade reaction, nucleophilic aldol addition of an alkynoate copper intermediate with aldehyde 35 formed product 36, which delivered the desired products 37 as a single (E)-stereoisomers through an elimination process in good to excellent yields [Scheme 8, Eq. (b)]. In the same year, an analogous cross-coupling reaction with α-diazo phosphonates 38 instead of EDA through a sequential alkynylation/aldol addition/Horner−Wadsworth−Emmons (HWE) type reaction was disclosed by the same group [98]. This method provided straightforward access to conjugated enynes 40 with good stereoselectivity and excellent functional group compatibility [Scheme 8, Eq. (c)]. Moreover, one C-C bond and one C=C bond were formed successively in a one-pot manner, making those novel enynes synthesis methods practically useful.

Allenylation Terminated by Protonation
As a complementary to Fu's method for the selective synthesis of alkynoates [89], in 2011, Fox's group reported a selective coupling reaction of α-substituted-α-diazoesters 41 with terminal alkynes 10 to the syntheses of allenoates in the presence of Cu(II) (trifluoroacetylacetonate) 2 and 3,6-di(2-pyridyl)-s-tetrazine L2 in DCE [99]. As a result, allenoates 43 were obtained as the main products with slight traces of the alkynoates. Key to the development of this selective method was the recognition of an adventitious base, potassium carbonate, which improved the selectivity of isomerization to form the allenoate products (Scheme 9). Scheme 9. Cross-coupling reaction of copper carbene with terminal alkynes for the synthesis of allenoates.
Later in 2013, an efficient copper-catalyzed cross-coupling between diazoacetamides 44 and terminal alkynes 10 under ligand-free conditions was developed by Sun [100]. This method provided a practical method for the assembly of substituted 3-butynamides 45 and dienamides 46. Interestingly, when sodium carbonate was added to the reaction mixture, the allenic compounds 46 were obtained as the main products. However, alkyne products 45 were generated as the major products in the absence of this base (Scheme 10). Moreover, the alkynoate compounds 45 could be smoothly converted into the isomeric allenes 46 in the presence of sodium carbonate without assistance of the copper catalyst. In the same year, Wang and co-workers developed a series of synthetic methods to form substituted allenes under optimized conditions in the presence of copper(I) complexes [101][102][103][104]. Diffident types of substituted diazo compounds and N-tosylhydrazones were employed as the carbene precursors for the coupling with various terminal alkynes, delivering the allenoic derivatives in good yields with a wide range of functional group tolerance (Scheme 11). Notably, ethyne 54 was also a compatible substrate for this reaction, which leads to a new synthetic method for the synthesis of terminal allenes 55 in moderate to excellent yields [104]. However, using one equivalent amount of CuI with DMF as the solvent is critical to the success of this transformation [Scheme 11, Eq. (d)]. In 2015, a copper-catalyzed coupling reaction between flow-generated unstabilized diazo compounds and terminal alkynes was reported by Ley's group, providing a practical method for the synthesis of di-and tri-substituted allenes 59 in high yields under mild conditions [105]. The unstable diazo compounds 57 were generated in situ from hydrazones 56 through oxidation with activated MnO 2 . Then, the above solution was injected directly into the other reaction mixture, which contained terminal alkynes 58, base, and CuI catalyst. The reaction delivered the allene products 59 in good to excellent yields. To highlight the selectivity and functional group compatibility of this protocol, norethindrone and propargylated quinine were successfully applied to the optimal reaction conditions, generating the corresponding products in 63% and 82% yields, respectively (Scheme 12). In addition to the diazo compounds, conjugated eneyne ketones 60 were introduced as carbene precursors by Wang and co-workers in 2016 in a copper-catalyzed cross-coupling reaction with terminal alkynes [106]. This reaction afforded trisubstituted allenes 61 in high yields with broad functional group tolerance under mild reaction conditions (Scheme 13). Scheme 13. Copper-catalyzed cross-coupling reaction of conjugated eneyne ketones with terminal alkynes.
In 2015, Feng and Liu contributed an asymmetric cross-coupling of α-diazoesters 15 with terminal alkynes 10 using chiral Cu(I)/ guanidine complex as the catalyst [107]. Notably, no additional base was necessary for this transformation, providing optically active 2,4-disubstituted allenoates 62 under mild reaction conditions in good to high yields (up to 99 %) with good to excellent enantioselectivities (Scheme 14).
In 2016, Wang and co-workers reported a highly enantioselective copper-catalyzed cross-coupling of aryldiazoalkanes 57 with terminal alkynes 10 [108]. By utilizing chiral Cu(I)/bisoxazoline ligand L4, this reaction delivered a series of trisubstituted allenes 63 in moderate to high yields (up to 96%) with excellent enantioselectivities (up to 98% ee). Unlike the previous works using CuI as the catalyst, Cu(MeCN) 4 PF 6 complex was used as the optimal metal catalyst to enable high reactivity and stereoselectivity in this reaction (Scheme 15). One year later, Ley's group reported their continuous flow strategy for the asymmetric coupling reaction of unstabilized diazo compounds 65 with propargyl amines 66 in the presence of chiral Cu(I)/PyBIM complex [109]. This method generated the amino-substituted chiral allenoates 67 in moderate yields (up to 57%) with high enantioselectivities (up to 96% ee) in a fast reaction rate (10-20 min) with a variety of functional group compatibility (Scheme 16).

Allenylation Terminated by Electrophilic Addition
In 2018, a one-pot copper-catalyzed asymmetric three-component reaction of diazoesters 15 with terminal alkynes 10 and isatins 68 was reported by Liu's group [110]. Axially chiral tetra-substituted allenoates 70 bearing a stereogenic center were obtained under a chiral Cu(I)/guanidinium salt/YBr 3 catalytic system with high diastereo-and enantioselectivities. In this work, the aldol type addition of allenoate-copper intermediates 69 with isatins 68 has been proposed as the key step in this reaction. Moreover, convincing experimental evidence for the formation of allenoate-copper intermediate 69 was provided through the synthesis of chiral allenoate, which was generated from the C-H insertion reaction of α-diazoester with alkyne. The author found that additional acids improved the catalyst efficiency of the chiral copper complex. The intramolecular nucleophilic trapping reaction of allenoate-copper intermediate with embedded aldehyde species was also successful, generating the cyclic allenoate product 73, albeit the yield and stereoselectivity were moderate (Scheme 17). Recently, Sun's group has realized an enantioselective intramolecular nucleophilic aldol addition of in situ formed allenoate-copper intermediate with aldehyde using chiral Cu(II)/Box complex [111]. Distinct from the previous version with copper(I) catalysts, this protocol used copper(II) salt as an optimal catalyst in this asymmetric cross-coupling reaction. The tetra-substituted allenoates 75 containing both central and axial chiralities have been obtained in moderate to good yields with good to excellent stereoselectivities. (Scheme 18).

Allenylation Terminated by Allylation
In 2016, Wang and co-workers realized the synthesis of allyl-substituted allenes through trapping of allenoate-copper intermediate with allyl bromide through a nucleophilic substitution process [106]. In this reaction, conjugated eneyne ketones 60 have been used as the carbene source. Mechanistically, the cooper-(2-furyl) carbene intermediate was generated in situ from eneyne in the presence of CuI, followed by a migratory insertion process to afford nucleophilic alkynoate copper intermediate 77 that was trapped by allyl halide 76 (Scheme 19). In this method, the choice of the base was pivotal for the reaction outcomes when K 2 CO 3 was employed as the base, affording 2-furyl substituted allenes 78 in generally good yields.

Cascade Transformations Involving Allenylation Process
Nucleophilic addition with allenoic ester or its isomeric compound is one of the generally used synthetic strategies for the expeditious construction of highly functionalized carbocycle or heterocycle structures [112][113][114][115][116][117][118][119][120]. Thus, a variety of inter-or intra-molecular cascade reactions have been developed through different nucleophilic addition processes of the allene derivatives that were generated from cross-coupling between alkynes and copper carbenes.
In 2011, a one-pot synthesis of phenanthrenes 81 via ligand-free CuBr 2 -catalyzed coupling reaction/intramolecular cyclization of terminal alkynes 23 with N-tosylhydrazones 79 derived from o-formyl biphenyls was developed by Wang and co-workers [121]. In this cascade reaction, allene intermediates 85 were initially generated through a cross-coupling reaction of N-tosylhydrazones 79 with terminal alkynes 23, followed by a 6π-cyclization and isomerization to deliver the phenanthrene products 81 with broad functional group compatibility (Scheme 20).
Later in the same year, instead of using o-aryl substituted N-tosylhydrazones, o-hydroxyor o-amino-substituted N-tosylhydrazones were introduced by the same group as carbene precursors in an analogous cascade transformation, a ligand-free CuBr-catalyzed coupling reaction/intramolecular cyclization sequence, achieving the synthesis of benzofuran or indole derivatives 84 in moderate to excellent yields [122]. The initially formed allene intermediates 83 were trapped through a nucleophilic addition by the embedded o-hydroxyor o-amino group to afford the cyclized products 84 (Scheme 21). Scheme 20. Copper-catalyzed allenylation followed by 6π-cyclization.
In 2011, a similar catalytic strategy was developed by Balakishan's group. They reported a simple procedure for the synthesis of aza-and oxa-cycles via a copper-catalyzed coupling reaction of functionalized terminal alkynes 85 with diazoesters 86 [123]. Initially, the allene intermediates were formed in the presence of CuI, followed by an intramolecular aza-or oxa-Michael cycloaddition and isomerization to generate the cyclized five-or six-membered products 87 in generally good yields (Scheme 22).
In 2015, a stereo-divergent synthesis of five-membered heterocycles was developed by Sun's group [124]. This work described a copper-catalyzed cross-coupling reaction and annulation cascade reaction of amino alkynes 88 with diazo compounds 15. The proposed reaction mechanism involves trapping in situ formed allene intermediates, yielding 2-methylenes 89 (when PG = Bn) and 2,3-dihydropyrroles 90 (when PG = Ts) in good yields with broad functional group tolerance under mild conditions. Control experimental results show that N-benzyl amino alkynes were more likely to form 2-methylenespyrroles derivatives 89 through 5-exo-dig cycloaddition, while 2,3-dihydropyrroles 90 generated from N-tosylamino alkynes through 5-endo-dig cycloaddition would be more favorable (Scheme 23). Scheme 23. Copper-catalyzed allenylation followed by divergent annulation.
In 2018, Sun and co-workers expanded the above chemistry to the synthesis of the fourto six-membered heterocycles with N-substituted prop-2-yn-1-amines 91 and diazoacetates 15 [125]. Generated allenoic species 92 have been proven as the key intermediates for the subsequent diverse annulations under optimized conditions toward functionalized heterocycle in moderate to good yields. Treatment of allenoates 92 with sodium phenolates led to six-membered products 93; silver nitrate and triethylamine yielded five-membered products 94; and what's more, four-membered products 95 were generated under lithium tert-butoxide conditions (Scheme 24). Scheme 24. Divergent synthesis of four-to six-membered heterocycles involving an allenylation process.
In addition to the cyclization through addition with a heteroatom, carbon-based nucleophilic species could also be served as the nucleophile to addition with these allenes, forming the C-C bond instead of the C-X bond [126,127]. In 2015, Kumaraswamy's group developed a cooper catalyzed cross-coupling reaction/intramolecular Michael addition cascade reaction [128], achieving the formation of indene and dihydronaphthalene derivatives 97 in good yields with broad functional group tolerance [Scheme 25, Eq. (a)]. Later in 2017, Sun's group reported an analogous approach toward five-or six-membered carbo-/heterocycles with diazo compounds 15 and alkyne-substituted malonates 98 [129]. In this reaction, the ligand significantly enhanced the reaction yields and inhibited the Coniaene side reaction. As a result, the polyfunctionalized cyclohexenes, tetrahydropyridines, and dihydropyrans have been prepared in moderate to high yields under mild reaction conditions [Scheme 25, Eq. (b)]. In 2015, a Cu(I)-catalyzed denitrogenative annulation reaction of pyridotriazoles 100 with terminal alkynes 10 was developed by Gevorgyan's group [130]. Initially, α-pyridyl copper carbenes were generated from pyridotriazoles 100 in the presence of the copper catalyst, followed by a cross-coupling reaction with terminal alkyne to form either propargylic or allenoic intermediates 101, which were terminated by copper-catalyzed cycloisomerization to furnish the indolizines 102 in moderate to excellent yields (Scheme 26).
In 2018, Wang and co-workers reported a copper-catalyzed geminal difunctionalization reaction of terminal alkynes [131]. The key step in this cascade reaction is trapping the in situ generated allenoic species 105 with a sulfonyl anion to form the carbon-sulfur bond, providing a variety of vinyl sulfones 106 in good yields with excellent stereoselectivities under mild reaction conditions. It was noted that the excellent stereoselectivities might be due to the influence of steric hindrance, and no ligand and additive was required in this transformation (Scheme 27).
Recently, Sun and co-workers have demonstrated a copper-catalyzed three-component reaction of terminal alkynes with diazo compounds and B 2 pin 2 for the synthesis of trisubstituted alkenylboronates [132]. In this alkyne difunctionalization transformation, the copper catalyst plays dual roles in the whole process. Initially, copper catalyzed the cross-coupling to form an allenoic intermediate, followed by a copper-catalyzed stereoselective boration reaction with B 2 pin 2 . When diazo compounds 53 were used as carbene precursors, the steric interaction forced the boron group to attack the β-carbon from the opposite side of the γ-phenyl group on the allenoic species 107, leading to the favored (Z)-isomers 108 as major products. Whereas, in the case with N-tosylhydrones 51 as carbene precursors, the addition of Cu-Bpin complex to corresponding allenoic species 109 provided allyl copper intermediate, which was more favored to form a six-membered ring transition state with the association of MeOH, finally furnishing the more thermodynamically stable (E)-products 110 (Scheme 28).
In 2016, Xu's group developed a chemo-divergent copper-catalyzed cascade reaction of alkynyl-tethered α-iminodiazoacetates 119, providing polycyclic and multi-substituted pyrroles in high yields with a broad substrate scope [168]. Especially, the tetra-substituted 3-formylpyrroles 124, which were difficult to access by alternate approaches. Mechanistic studies indicated that the α-imino carbene 120 is the key common intermediate in this divergent reaction, which was generated by metal-catalyzed carbene/alkyne metathesis of the alkynyl-tethered diazo compounds 121. When R 1 , R 2 was imbedded with an aromatic ring, polycyclic pyrroles 122 were formed as the major products through a [3+2]cyclization and aromatization process. Whereas, for substrates with a methoxy group on the nitrogen (R 2 = OMe), the carbene intermediate underwent an N-O insertion/alkoxy migration/alcoholysis sequence, giving the 3-formylpyrrole products 124 in generally good to excellent yields (Scheme 32). At the same time, Xu and co-workers also developed a copper-catalyzed carbene/alkyne metathesis cascade reaction with alkyne-tethered diazo compounds 125 [169]. This transformation provided a rapid access for the construction of multi-substituted 4-carboxyl quinoline derivatives 127 in high to excellent yields. In this cascade reaction, one C=N and one C=C bond were formed with the assistance of the copper catalyst under mild reaction conditions [Scheme 33, Eq. (a)]. Later in 2017, Ye's group reported an analogous protocol by using ynamides 128 as carbene precursor [170]. In this work, a copper carbene was generated in situ through a catalytic oxidation process in the presence of quinoline N-oxide, followed by a CAM process and terminated by carbene reaction with an embedded azide group, providing a wide range of pyrrolo [3,4-c]quinolin-1-ones 130 in good yields [Scheme 33, Eq. (b)]. These works represented a practical method for the dual functionalization of alkynes.
In addition to the nucleophilic addition of the in situ formed copper carbene intermediates, electrophilic aromatic substitution or C(sp 2 )-H bond functionalization is another useful terminating transformation for the direct construction of polycyclic fused frameworks. In 2017, Doyle's group reported a copper-catalyzed intramolecular cascade reaction of diazo compounds 131. This transformation went through a CAM process followed by a carbene C(sp 2  Notably, this reaction described a rare example of the Buchner reaction with donor/donor type metal carbene species [172]. In 2018, Xu and co-workers developed an intermolecular copper-catalyzed formal CAM process [173], which underwent a copper promoted [3+2]-cycloaddition/dinitrogen exclusion/nucleophilic addition process, providing a direct and effective access to 2Hchromene derivatives 139 in generally good to high yields. Mechanistic studies indicated that the 3H-pyrazole 138 is the key intermediate in this cascade transformation, and this critical intermediate was isolated and confirmed by single-crystal X-ray diffraction and spectroscopy analysis for the first time (Scheme 35). Based on a similar protocol, a copper-catalyzed formal [1+2+2]-annulation of alkynetethered diazo compounds 140 with pyridines 141 has been reported by Xu's group recently [174]. In contrast to the previously reported cascade reaction that terminated the copper carbene intermediate on the carbonic center, a vinylogous addition of vinyl carbene intermediate with pyridine derivatives occurred in this reaction, followed by an intramolecular annulation to form cycloadducts 146, which underwent a decarboxylative aromatization process to form the desired polycyclic fused indolizine derivatives 147 in good to high yields (Scheme 36, path a); although, direct formal [3+2]-cycloaddition via pyridinium ylide pathway could not be ruled out so far (Scheme 36, path b).

Conclusions
This review has summarized the recent progress of catalytic alkyne functionalization involving copper carbene intermediates. Copper carbene species derived from different carbene precursors have been introduced to react with alkynes through two distinguished reaction models: the cross-coupling reaction of copper carbene intermediates with terminal alkynes and the addition of copper carbene intermediates onto the C-C triple bond. The former reaction involves alkynoate or allenoate copper intermediates, followed by protonation, nucleophilic substitution, electrophilic addition, or elimination process, yielding functionalized alkynes and allenes, respectively. The latter version includes cyclopropenation and cascade reaction via carbene/alkyne metathesis process. Although substantial progress has been realized in this field, challenges remain, e.g., the carbene precursors are still mainly limited to the diazo compounds; the catalytic efficiency could be further improved, especially in the asymmetric catalysis; and synthetic applications of this chemistry are still under exploration. Therefore, the synthetic potential of this chemistry could be envisioned through the introduction of a variety of readily accessible carbene precursors and with the development of robust copper catalysts/ligands, including novel methodology discovery for the catalytic alkyne functionalization, and expeditious assembly of molecules with structural complexity and diversity for the leading compound development.
Author Contributions: Conceptualization, K.D. and X.X.; writing-original draft preparation, K.D. and X.X.; writing-review and editing, K.D., M.L. and X.X.; funding acquisition, X.X. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest:
The authors declare no conflict of interest.
Appendix A