Although transition metal-catalyzed hydroarylations of alkynes are very useful, they require expensive rhodium or palladium catalysts, as well as additional ligands and/or additives. A few examples of catalysts based on inexpensive first-row transition metals, such as nickel and cobalt, have been reported, but they have seen limited development as compared to rhodium and palladium catalysts.⁵ We have independently developed a hydroarylation of internal alkynoates with arylboronic acids using inexpensive copper catalysts, such as CuOAc or Cu(OAc)₂, in methanol at ambient temperature, which selectively afforded syn-hydroarylation products.⁶ Furthermore, neither ligands nor additives are required in this reaction. Thus, the Cu-catalyzed hydroarylation of alkynoates provides easy access to synthetically valuable β,β-disubstituted acrylates.

With the abovementioned features, the Cu-catalyzed hydroarylation of internal alkynoates has been applied to the synthesis of various heterocyclic motifs, which are found in natural products and pharmaceutically important compounds. For example, 4-arylbutenolides, 4-arylpentenolides, and 4-arylcoumarins have been synthesized from alkynoates having an alcohol or phenol moiety on the alkyne terminalvia tandem Cu-catalyzed hydroarylation/lactonization processes.^7,8 Representative examples are shown in Scheme 1. Notably, hydroarylation/coumarin formation enabled the efficient synthesis of seven natural neoflavones.

Nitrogen heterocycles have also been synthesized by Cu-catalyzed hydroarylation, as shown in Scheme 2.^9,10,11 The hydroarylation product derived from (o-nitrophenyl)alkynoate 1 was converted into 3-phenyl-indole-2-carboxylate 2 in high yield via Mo-catalyzed Cadogan cyclization.^9,12 Hydroarylation of the orthogonally protected (o-amino-phenyl)alkynoate 3 could be performed under similar conditions to afford an N-benzyl-4-aryl-2-quinolone after acidic removal of the Boc group.¹⁰ Because of the bulky protected o-aminophenyl moiety, protodeboration of the arylboronic acid proceeded faster than the desired hydroarylation. Thus, arylboronic acid 2,2-dimethyl-1,3-propanediol esters, such as 4, should be used to suppress the undesired protodeboration. The use of a sterically more demanding pinacol ester retarded the reaction, thus diminishing the product yield. This tandem hydroarylation/lactamization process could be successfully applied to the synthesis of a natural alkaloid and relevant derivatives.¹¹

Besides alkynoates, other electron-deficient alkynes have also been used as substrates for Cu-catalyzed hydroarylation. The hydroarylation of 3-aryl-2-propynenitriles stereoselectively affords 3,3-diarylacrylonitriles,¹³ and this method has been successfully extended to the synthesis of antitumor agent CC-5079 (Scheme 3).¹⁴ Since the biological activity of CC-5079 strongly depends on its olefin geometry,¹⁵ Cu-catalyzed hydroarylation is quite useful as it affords both stereoisomers in a stereospecific manner. Trifluoromethyl groups also function as electron-withdrawing groups, as Cu-catalyzed hydroarylation efficiently proceeds with (trifluoromethyl)-alkynes, affording valuable tri-substituted (trifluoromethyl)alkenes.¹⁶ Thus, the Cu-catalyzed hydroarylation of (trifluoromethyl)alkyne 4 with (o-nitro)phenylboronic acid stereoselectively furnished trisubstituted alkene 5, which was further transformed into 3-aryl-2-(trifluoromethyl)indole 6 in high yield via the modified Cadogan cyclization (Scheme 4).¹⁷

Enantioselective conjugate reduction of β,β-diaryl-α,β-unsaturated carbonyl compounds provides efficient access to chiral 1,1-diarylalkyl motifs, which are frequently found in bioactive molecules. Therefore, stereoselective construction of the required unsaturated carbonyl precursors is crucial, and Cu-catalyzed hydroarylation has been used for this purpose.¹⁸ As a demonstration of this strategy, Yun and co-workers reported the enantioselective synthesis of (R)-tolterodine,¹⁹ a potent muscarinic antagonist, via Cu-catalyzed asymmetric conjugate reduction of a 3,3-diarylacrylonitrile (Scheme 5).²⁰ The required acrylonitrile precursor 8 was obtained in 71% yield via Cu-catalyzed hydroarylation of cyanoalkyne 7 bearing an unprotected phenol moiety with phenylboronic acid. Subsequent asymmetric conjugate reduction of 8 with polymethylhydrosiloxane (PMHS) as the reducing agent was performed in the presence of 2 mol % Cu(OAc)₂ and 2 mol % chiral ligand 9 ((R)-(S)-Josiphos) in toluene at room temperature, affording the desired saturated 3,3-diarylpropanenitrile 10 in 86% yield and with 96% ee. Finally, 10 was transformed to (R)-tolterodine in 63% yield over two steps.

When allylboronate was used instead of arylboron reagents under the Cu-catalyzed hydroarylation conditions, hydroallylation products were obtained with high regio- and stereoselectivities. Notably, this mild Cu-catalyzed protocol selectively produced 1,4-dienes in good yields, although such a skipped diene tends to undergo isomerization to a more stable 1,3-diene (conjugate diene). Hydroallylation proceeded with alkynylamide 11b and alkynylsulfone 11c, in addition to alkynoates and cyanoalkynes (Scheme 6).²¹ The introduced allyl moiety could be employed as a synthetic handle for subsequent transformations, such as hydroboration/oxidation or hydroboration/Suzuki-Miyaura coupling. The interesting bicyclic butenolide 15 was also synthesized from 1,6-enynoate 13 via sequential hydroallylation/ring-closing metathesis.²² Furthermore, Kong, Zhu, and co-workers reported the hydroallylation of thioalkynes, such as 16.²³ In this case, modified conditions with a mixed solvent (MeOH/THF, 1:3) improved the product yield. The obtained product 17 could be used for nickel-catalyzed cross coupling with Grignard reagents via C-S bond cleavage.

A disadvantage of Cu-catalyzed hydroarylation and hydroallylation is that they are restricted to the synthesis of trisubstituted alkenes. Hence, an alternative method to synthesize tetrasubstituted alkenes was developed by Sawamura, Ohmiya, and co-workers: the three-component coupling of an alkynoate, alkyl-9-BBN 18, and ⁿBu₃ SnOMe proceeded in the presence of catalytic amounts of CuOAc and^tBuOK in dioxane at 60 °C, affording alkenylstannane 19 in 74% yield with a syn/anti ratio of 97:3 (Scheme 7).²⁴ The obtained product could be utilized as a substrate for various cross-coupling reactions. When adding ^tBuOH instead of ⁿBu₃SnOMe as the proton source, hydroalkylation product 20 was also obtained quantitatively.²⁵ In this case, the use of P(OPh)₃ as the ligand was necessary to achieve a complete syn selectivity.

In summary, Cu-catalyzed hydroarylation of electron-deficient alkynes with arylboron reagents has been developed as an efficient protocol for the regio- and stereoselective synthesis of valuable trisubstituted alkenes with a functional group under mild conditions. This method is also intriguing because inexpensive copper acetates act as catalysts, and neither ligands nor additives are required. The broad substrate scope of this Cu-catalyzed hydroarylation has been exploited for the synthesis of important heterocyclic compounds, including butenolides, pentenolides, coumarins, indoles, and 2-quinolones. Moreover, the protocol was extended to hydroallylation and hydroalkylation/stannylalkylation using allylboronates or alkylborons, respectively, instead of arylboron reagents. In the future, these methods are expected to find broad application in the synthesis of natural products, functional materials, and bioactive molecules.