Copper-catalyzed functionalization of enynes

The copper-catalyzed functionalization of enyne derivatives has recently emerged as a powerful approach in contemporary synthesis. Enynes are versatile and readily accessible substrates that can undergo a variety of reactions to yield densely functionalized, enantioenriched products. In this perspective, we review copper-catalyzed transformations of enynes, such as boro- and hydrofunctionalizations, copper-mediated radical difunctionalizations, and cyclizations. Particular attention is given to the regiodivergent functionalization of 1,3-enynes, and the current mechanistic understanding of such processes.


Introduction
The desire to build complex, functionalized molecules rapidly and efficiently from simple precursors is a recurring theme in modern organic chemistry. Many envision a sustainable future in which the processing of feedstock substrates in catalytic and step-/atom-economical transformations will allow new regions of chemical space to be explored. 1 The transition-metal catalyzed functionalization of olens is seen as an approach with the potential to contribute to such a future, 2 as it has proved capable of delivering high-value, multifunctionalized, stereo-dened products. Copper catalysts hold particular promise for fullling goals pertaining to sustainability, as copper is more abundant 3 and less toxic 4 than other transition metals. Indeed, various olens 5 have been transformed into densely functionalized products 6 using copper catalysis. In particular, enynes are highly versatile substrates. They can be obtained using numerous, efficient catalytic methods 7 and their ambident reactivity has been exploited to deliver a multitude of products. 5f, 8 Herein, we will review the copper-catalyzed functionalization of enynes. This fast-growing eld has seen the implementation of various strategies in copper catalysis, such as hydro-and borofunctionalizations, multicomponent reactions, radical difunctionalizations, and cyclizations. The copper-catalyzed functionalization of enynes will be discussed in four sections: (1) borofunctionalization, where a copper-boryl complex is the catalytically active species; (2) hydrofunctionalization, where a copper-hydride complex is the catalytically active species; (3) copper-mediated radical difunctionalization, and; (4) coppercatalyzed functionalization of non-conjugated 1,n-enynes. Generally, 1,3-enynes are the most common substrates in these processes and a variety of highly useful products are accessible (Scheme 1); for example, enantioenriched, (homo)propargylic compounds (1,2-functionalization), allenes (1,4-functionalization), and dienes (4,3-/3,4-functionalization), are important in synthetic 9 and/or medicinal chemistry. 10 different stages of the catalytic cycle: the chemo-(alkene vs. alkyne) and regioselectivity (e.g. 1,2-vs. 2,1-addition) of the rst functional group (FG 1 ) addition, the possible isomerization of organocopper intermediates, and the mechanism of the second functional group (FG 2 ) addition. Details of these mechanisms will be presented when appropriate and when experimental evidence or DFT calculations are available. In general terms, the possible products can be grouped into two families (Scheme 2)it is the chemoselectivity of the reaction with the rst functional group (FG 1 ) that determines which family of product forms. Other products are theoretically possible, however, Scheme 2 summarises the types of products that have been accessed to date. If the initial functionalization occurs at the olenic component of the enyne (the ene-pathway), the (homo) propargylic/allenic family of products is formed. Alternatively, reaction of FG 1 with the alkyne component (yne-pathway) leads to the diene family of products. Within each family are subgroups that are accessed through different modes of addition to the enyne. For example, in the ene-pathway, 1,2-functionalization leads to (homo)propargylic products, whereas 1,4-functionalization leads to allenic products. The notation used to describe the type of functionalization refers to the position of the attached functional groups in the product, i.e. the (homo) propargylic product is said to form via a 1,2-functionalization as the rst functional group (FG 1 ) is attached to C1 and the second functional group (FG 2 ) is attached to C2. Using the same concepts, the yne-pathway leads to diene products of either 4,3or 3,4-functionalization. This is a simplied model for describing the outcomes of these reactions and a similar nomenclature will be used throughout this perspective. There are numerous pathways by which enynes can react and a detailed description of each mechanistic pathway is beyond the scope of this review, however, key aspects will be highlighted.

Borofunctionalization
Boron-containing compounds are involved in 11% of the C-C bond forming reactions used in process chemistry. 1d Since the seminal reports of Miyaura 11 and Hosomi 12 on the borylation of enones, the copper-catalyzed borylation of olens has become a versatile starting point for the design of important multicomponent reactions. 5c,5d,13 Thus, it is not surprising to nd these processes at the heart of several seminal reports on the copper-catalyzed functionalization of 1,3-enynes.

Regiodivergent processes
The copper-catalyzed boroprotonation of 1,3-enynes 1 reported by Ito and co-workers 14 in 2011 introduced some useful concepts concerning the regioselectivity of enyne functionalization (Scheme 3A). The system used a Cu-Bpin catalyst, formed in situ from a Cu-alkoxide and B 2 pin 2 , and MeOH as a proton source. The reaction of relatively simple enynes, for example butyl-1,3-enyne 1a and phenyl-1,3-enyne 1b, provided the 1,2 products 2a/2b with high regioselectivity with ligands L1 and L2 (Scheme 3B). The authors then explored the effect of substitution on the alkene moiety of the enyne and observed a ligandcontrolled regioselectivity switch. Thus, 1-substituted enynes gave the 1,2-product 2c with the bidentate XantPhos ligand L1, whereas the 4,3-product 3a was obtained when using monodentate PPh 3 L2. Conversely, 1,2-disubstituted enynes always gave the 4,3-product 3b no matter which ligand was used, possibly due to the steric hindrance around the olen. The authors also reported a moderately enantioselective 1,2-boroprotonation. Frontier orbital population analysis from DFT calculations was used to explain the regioselectvity of these results (Scheme 3C). The most important interaction to consider is between the HOMO of the copper-boryl complex and the LUMO of the enyne. In this regard, the larger coefficients at C1 and C4 explain the preference for 1,2-/4,3-functionalization. However, a detailed discussion of the observed regiodivergency was not provided.
DFT studies were carried out on the two stereodetermining steps of this reaction (Scheme 5C). Firstly, the 1,2-borocupration was proposed as the enantiodetermining step of the process. This step proceeds through attack of a Cu-Bpin species at the C-C double bond of the enyne through a 4membered transition state TS-1. Attack on the Si face of the enyne was favoured by 2.1 kcal mol À1 over attack on the Re-face. The resulting propargyl-copper species int-1 can then isomerise via TS-3 to give the corresponding allenyl-copper species int-2 (Scheme 5D). Although this step was not investigated in this report, the propargyl-allenyl isomerisation of transition metal complexes is a well-known phenomenon that has been studied using DFT calculations and X-ray crystallography. 17 Finally, the desired product was proposed to form through the coupling of the allenyl copper species int-2 and the aldehyde 6 in a diastereo determining, closed, 6-membered transition-state (TS-2, Scheme 5C). Other transition states (e.g. involving attack on the other face of the aldehyde) were modelled but were disfavoured by at least 1.9 kcal mol À1 .
Following on from this report, Yin and co-workers 18 published consecutive papers on the copper-catalyzed borylative 1,2-functionalization of 1,3-enynes 1 with ketones 8 (Scheme 6A). Firstly, Jia, Yin et al. 18a described the coupling of aryl and alkyl-substituted enynes with peruoroalkyl ketones (Scheme 6B). Using Ph-BPE L5, a ligand that has found much use in the eld of copper-catalyzed functionalization of olens, very good to excellent yields and excellent enantioselectivities were obtained across a wide range of aryl and alkenyl triuoromethyl ketones. Similarly, longer peruoroalkyl chains were also well tolerated. Yin and co-workers 18b then extended their work towards the use of aryl, alkyl ketones (Scheme 6C). The conditions were similar to those used in their previous report, however, the addition of a non-coordinating counter-anion NaBArF was required to obtain high yields. Excellent enantioselectivities were observed across all ketone inputs, and both aryl and alkyl-substituted 1,3-enynes were good substrates. In both reports, the authors chose to oxidize the products upon workup to afford the anti-homopropargylic alcohols 9.
In 2020, Procter and co-workers 19 developed the coppercatalyzed borylative 1,2-functionalization of 1,3-enynes 1 with aldimines 10 to give anti-homopropargylic amines 11 (Scheme 7). Interestingly, Ph-BPE L6 was again the ligand of choice. A range of electron-rich and electron-decient N-phosphinoyl imines coupled to enynes in very good yield and with excellent diastereo-and enantiocontrol. The authors found that a switch in solvent, temperature and copper catalyst ensured favourable reactivity with a wide range of enynes. The products were oxidized during work-up to afford the 1,3-aminoalcohols 11. Importantly, the reaction was extended to 1,2-disubstituted (E)enynes (11e and 11f) to give products containing 3 contiguous stereocenters with high enantiocontrol.

1,4-Borofunctionalization processes
In 2020, Xu and co-workers 20 developed the copper-catalyzed 1,4-boroprotonation of 2-triuoromethyl-1,3-enynes 1. A ligand-free CuBr catalyst promoted the formation of aryl and alkyl-substituted allenes 12 in very good to excellent yields (Scheme 8A and B). An efficient enantioselective process that, unusually, did not require a base was also developed using the bisoxazoline ligand L7 (Scheme 8C). Interestingly, in some cases, the authors observed minor amounts of the 1,2-boroprotonated product, although no clear explanation for variation in regioselectivity was put forward. Furthermore, a related 1,4-silaprotonation operating under similar conditions exhibited high functional group tolerance and allowed access to the 1,4-silaprotonated products 12g-12i with high enantiocontrol (Scheme 8D).

Hydrofunctionalization
With origins in the 1850s, 23 copper hydride chemistry gained popularity with the introduction of Stryker's reagent 24 [(PPh 3 ) CuH] 6 and its use for the selective reduction of carbonyl derivatives. Signicant advancements by Buchwald, 25 Lipshutz 26 and others 23 led to catalytic asymmetric reactions using copper hydride species. The application of copper hydride chemistry in processes involving enynes is particularly appealing as it allows facile access to propargyl and allenyl metal species that react selectively under mild conditions.

1,2-Hydrofunctionalization processes
In 2016, Buchwald and co-workers 27 reported an efficient copper-catalyzed 1,2-hydrofunctionalization of enynes 1 with ketones 17 to give highly substituted and enantioenriched homopropargyl alcohols 18 (Scheme 11A). The suitability of various enyne inputs was demonstrated and the process showed excellent diastereo-and enantioselectivity. The reaction tolerated both electron-donating and electronwithdrawing substituents on the aryl ring of the ketone. Notably, the antifungal medication terbinane, which contains an enyne unit, responded well to hydrofunctionalization to give 18d (Scheme 11B).
A full mechanistic prole for the reaction was provided by DFT calculations (Scheme 12). The catalytic cycle begins with an enantioselective 1,2-hydrocupration of the enyne by the in situ generated copper hydride int-4, to give propargyl-copper species int-5 via a 4-membered transition state TS-4. It was found that attack on the Si face of the olen was favoured by 5.5 kcal mol À1 and that the selectivity arises from minimisation of steric interactions between the alkynyl group and the phenyl groups of ligand L6. A facile, exergonic, and stereospecic 1,3-isomerization of int-5 through TS-5 led to the thermodynamically more stable allenyl-copper intermediate int-5 0 . The intermediate int-5 0 then undergoes coupling with the Re face of the ketone 17 through a 6-membered cyclic transition state TS-6 to afford int-6. This step was rendered highly diastereoselective through the minimisation of unfavourable gauche interactions between the ketone and int-5 0 , and between the ligand and the allenyl substituents. Protonation of int-6 delivers the homopropargyl alcohol products 18. Clear parallels can be drawn between this mechanism and that proposed by the Hoveyda group (Scheme 5). These mechanisms also likely underpin the transformations in Schemes 6 and 7.
The mechanism of the reaction was investigated by DFT (Scheme 13C). As previously described (Scheme 12), hydrocupration and 1,3-isomerization to the allenyl copper int-7 was found to be facile and exergonic. Subsequent coupling with nitrile 19 proceeds via the 6-membered transition state TS-7 to deliver the 1,2-functionalized species int-8 and is reminiscent of the addition to imines (Scheme 7). In related procedures, the catalytic cycle would usually close at this point to give functionalized (homo)propargylic products, however, in this case, a cyclization through transition state TS-8, followed by a 1,5proton shi gave substituted pyrroles 20. Small quantities of a side product resulting from 1,4-functionalization were also observed during the reaction.
Intrigued by the lower enantioselectivities observed for electron poor substrates, mechanistic experiments and DFT calculations were conducted and the results provided important insight into the stereochemical integrity of the allenyl-copper intermediate (Scheme 14C). In agreement with the work of Buchwald et al. (Scheme 12), hydrocupration of the (Re)-face of the enyne was found to be enantiodetermining. A facile, stereospecic 1,3-isomerization then led to the allenyl-copper species int-10. The lower enantioselectivities observed for some substrates was proposed to arise from epimerization of intermediate int-10 via the propargyl anion-type transition state TS-9. Furthermore, this epimerization was shown to be more facile for electron-poor enynes e.g. that give 21c (Scheme 14C). Low-temperature NMR kinetic studies on the epimerization of the related allenyl-copper species derived from the substrate that gives 21d, found the epimerization barrier to be similar to those calculated by DFT (Scheme 14C). Finally, formation of the allenyl-Bpin product 21 and regeneration of the copper-hydride catalyst occurs via the 4-membered transition state TS-10.
In 2019, an asymmetric semireduction of 1,3-enynes 1 was described by Buchwald and co-workers 30 using 2,4,6,8-tetramethylcyclotetrasiloxane (TMCTS) as a hydride source. As is now established in these processes, the Ph-BPE ligand L6 provided the best results. A range of aryl and alkyl-substituted 1,3-enynes, including those bearing sensitive functional groups, gave the allene products 23 with high enantioselectivity. Furthermore, the methodology was applied in an enantioselective synthesis of the natural product laballenic acid 23b, without the need for protection of the acid group.
In 2018, Hong, Ge and co-workers 31 reported the copperhydride catalyzed allenylation of quinoline N-oxide 24 using enynes 1 and affording enantioenriched N-heteroarylsubstituted allenes 25 (Scheme 16). In this case also, the Ph-BPE ligand L6 provided the best results. Aryl and alkylsubstituted 1,3-enyne inputs, as well as various heterocyclic Noxides, gave heteroaryl substituted allene derivatives with high enantioselectivity. Aryl-substituted 1,3-enynes bearing electrondonating (25a) and electron-withdrawing groups (25c) were tolerated, although, as seen by Hoveyda and co-workers (Scheme 5), electron-poor and ortho-substituted aryl-1,3enynes gave lower enantioselectivities (25c). Compatibility with some natural products, such as a vitamin E (to give 25f) and a cholesterol derivative, was also shown. DFT calculations showed that, in accordance with previous reports by Buchwald and Hoveyda, stereospecic isomerization follows enantioselective 1,2-hydrocupration to give the allenyl copper complex int-12. Coupling of allenyl-copper int-12 with the N-oxide was proposed to go through a 5 membered-transition state TS-12 to give int-13. A related 7-membered transition state leading to the propargylic product was found to be disfavoured by 3.5 kcal mol À1 . Finally, The N-O silylated adducts int-14 rearomatized spontaneously during work-up.

Copper-catalyzed radical functionalization of enynes
The addition of radicals to olens is an essential tool for C-C bond formation in organic synthesis. 32 Copper, with several readily accessible oxidation states, can mediate single-or two-electron processes and thus facilitate an array of redox processes that convert enynes to functionalized products. 33
The authors studied the origin of regiodivergency using DFT (Scheme 17C). When using L11, delocalized radical int-15a can be trapped by the copper(II)cyanide complex at both the propargyl and allenic positions. Thus, the regiodetermining step was found to be the reductive elimination, which proved easier for the allenyl-copper species int-16b leading to the observed 1,4-disubstituted allenes 28. On the Scheme 17 Lin and Liu's trifluorocyanation of 1,3-enynes.
other hand, trapping of radical int-15a at the less congested, propargylic site with the bulky copper(II) complex derived from L12 was favoured. Thus, the authors suggest that regioselectivity is controlled by the reductive elimination step when using non-bulky ligands, while trapping of the radical int-15a determines the outcome of the reaction when using sterically demanding ligands.

1,4-Functionalization
In 2019, Zhang, Bao and co-workers 36 reported a coppercatalyzed regioselective 1,4-carbo-/aminocyanation of 1,3enynes 1 using trimethylsilyl cyanide (TMSCN) (Scheme 19A). A wide range of 1,4-carbocyanated allenes 32 was obtained using alkyl diacyl peroxide (to give 32a) or alkyl iodide (to give 32b) radical precursors 31 (Scheme 19B). 1,4-Aminocyanated allenes 32c and 32d were also obtained in good yields using N-uorobenzenesulfonimide (NFSI) as the precursor of a Ncentered radical. 2-Substituted enynes were used in all cases (R 2 ¼ aryl/alkyl). Substitution on the terminus of the alkene in the 1,3-enynes was also tolerated (R 3 s H). In these cases, diastereocontrol was found to be dependent on the nature of R 2 . The authors proposed a mechanism in which copper promotes the formation of a C-centered (or N-centered) radical (Scheme 19C), followed by radical addition to the alkene moiety of the 1,3-enyne to give allenyl radical int-17, whose intermediacy was ascertained by radical probe experiments. Interestingly, the cyanation was proposed to occur from a copper(II)isocyano complex int-19a (detected by IR spectroscopy) rather than copper(II)cyanide complex int-19b. This raises the possibility that an alternative mechanism for cyanation might be occurring in the report by Lin, Liu et al. (Scheme 17). DFT studies suggested that the energy barrier to cyanation through TS-13, from int-19a, was 13.5 kcal mol À1 lower in energy than the analogous step with int-19b. The higher diastereoselectivites observed when R 2 ¼ aryl were proposed to arise from a favourable p-p stacking interaction with the ligand 1,10-phenanthroline L11b.
Bao and co-workers 37 later reported a related transformation using aryl boronic acids in place of TMSCN to access 1,4difunctionalized allenes 34 (Scheme 20A). A wide range of tetrasubstituted allenes bearing various aromatic and aliphatic groups was obtained in good yields (Scheme 20B). Mechanistic studies provided support for a radical mechanism and the authors suggested a catalytic cycle related to that shown in Scheme 19. Attempts to develop an asymmetric variant were unsuccessful.
The copper-catalyzed asymmetric addition of 1,4-enynes to ketones was reported by Kanai and co-workers 40 in 2017 (Scheme 21A). Alkyl and aryl-substituted 1,4-enynes gave functionalized 1,3-enyne products 36 with complete Z-selectivity, good to excellent enantioselectivity, and in very good yield with the commonly used ligand L6. A wide range of functional groups was tolerated and no base was required; the 1,4-enynes are initially deprotonated by the L6$CuMes complex, and then by the copper-alkoxide species int-21 formed during the catalytic cycle.
The mechanism was studied by Qin and co-workers 41 using DFT (Scheme 21C). Calculations showed that pre-catalyst L6$CuMes deprotonates 35, producing the allylcopper int-20. A 6-membered chair-like transition state TS-14, in which the larger phenyl group of the ketone occupies a pseudo-equatorial position and the Re-face of the ketone is attacked is invoked to account for the selectivity of the process. The cycle is closed by deprotonation of 35 by the copper-alkoxide complex int-21 via TS-15. The deprotonation of the enyne via TS-15 was proposed to be the rate determining step of the process.
In 2013 Lin and co-workers 42 reported a copper-catalyzed asymmetric borylative desymmetrization of cyclohexadienones 37 bearing a 1,6-enyne functional group. The cyclization reactions proceeded with high regio-and enantiocontrol to yield cis-dihydrobenzofuran derivatives 38 (Scheme 22A and B). cis-Products were exclusively obtained in moderate to good yield using the phosphoramidite ligand L14. Competing conjugate borylation is thought to be suppressed by the steric hindrance imposed by the neighbouring (R 2 ) substituent. Furthermore, the regioselectivity of alkyne borylation is thought to arise from the oxygen in the tether, coordinating and directing copper to the b-position of the alkyne. In 2019, the same group 43 (Scheme 22C) reported the silylative variant using Suginome's reagent (PhMe 2 Si-Bpin) and (R,R)-Ph-BPE L5.  In 2014, Li and co-workers 45 disclosed the copper-catalyzed cascade cyclization of 1,7-enynes 42 using sulfonyl chlorides 43 as coupling partners, affording substituted benzo[j]phenanthridin-6(5H)-one scaffolds 44 (Scheme 24). The mechanism of this reaction was not explored by the authors, but they proposed that an aryl radical or aryl-copper species, formed from the aromatic sulfonyl chloride, rst reacts at the alkynyl moiety, which triggers a cascade process to deliver products 44

Conclusions
In recent years, copper-catalyzed transformations of readily available enynes have allowed the construction of densely functionalized scaffolds, oen in an enantioselective fashion. Chemical Science Due to the ambident nature of enynes and the versatile reactivity of copper, a range of products are accessible by the careful marriage of substrate and catalyst class. We have highlighted examples of processes being used in the functionalization or preparation of bioactive molecules (e.g. Schemes 11,15 and 16). In addition, copper-catalyzed functionalizations of enynes have begun to nd application in total synthesis (Scheme 25). For example, Hoveyda et al. 16 have constructed known fragments of tylonolide and mycinolide IV using the enantioselective borofunctionalization of enynes with aldehydes. Similarly, Fürstner, Müller and co-workers utilized a related hydrofunctionalization in an approach to the cytotoxic natural product nannocystin Ax. 46 We expect to see further applications of copper-catalyzed enyne functionalization in future target molecule syntheses. To nd widespread application, some key challenges in this area need to be overcome. For example, our understanding of, and our ability to predict, the regioselectivity of a given process will aid in synthesis planning. With regard to boro-/hydro-functionalization, methods that expand the scope of effective aromatic enyne substrates are needed, as electronpoor and hindered aromatic enynes are oen unsatisfactory substrates (see Schemes 5,14 and 16). Ultimately, the ability to design more efficient and more powerful processes will be key in a future shaped by sustainable catalysis.

Conflicts of interest
There are no conicts to declare.