TSpace Research Repository - tspace.library.utoronto.ca

Catalytic Alkyne Dimerization without Noble Metals

Qiuming Liang, Kasumi Hayashi, and Datong Song

Version Post-Print/Accepted Manuscript

Citation Liang, Q., Hayashi, K., & Song, D. (2020). Catalytic Alkyne (published version) Dimerization without Noble Metals. ACS , 10(9), 4895-4905.

Publisher’s Statement This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Catalysis, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acscatal.0c00988

How to cite TSpace items Always cite the published version, so the author(s) will receive recognition through services that track citation counts, e.g. Scopus. If you need to cite the page number of the author manuscript from TSpace because you cannot access the published version, then cite the TSpace version in addition to the published version using the permanent URI (handle) found on the record page.

This article was made openly accessible by U of T Faculty. Please tell us how this access benefits you. Your story matters.

Catalytic Alkyne Dimerization without Noble Metals Qiuming Liang,† Kasumi Hayashi,† and Datong Song*

Davenport Chemical Research Laboratories, Department of , University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada ABSTRACT: 1,3-Enynes are core structures of various natural products or pharmaceuticals and are broadly used synthons in organic synthesis. Metal-catalyzed alkyne dimerization is a desirable preparation method, due to its perfect atom economy and the readily available alkyne substrates. Controlling the regio- and stereo-selectivity remains a challenge, due to the competing formation of the head-to-tail (gem) and head-to-head (E/Z) isomers. Although catalytic systems based on noble metals have been extensively studied, there has been a growing interest to replace these noble metals with environmentally benign and inexpensive alternatives. In this Perspective Article, we highlight recent advances in catalytic alkyne dimerization, without the use of noble metals. KEYWORDS: homogenous catalysis, base metal, alkyne dimerization, enyne, synthetic methods

and insertion of a second alkyne into the metal–hydride bond; INTRODUCTION the product is then released from the metal center through re- The conjugated enynes are prevalent structural motifs in nat- ductive elimination, which regenerates the low valence metal ural products, synthetic compounds with biological activities, center. Along Pathways A and B, the relative orientation of two organic materials, and useful synthons in organic synthesis.1–11 organo-ligands in the intermediate preceding the C–C bond for- The known synthetic routes towards conjugated enynes include mation step (i.e., A1/2 and B1/2) determines which enyne prod- Sonogashira cross-coupling reaction of terminal alkynes and vi- uct is formed. Similarly, the orientation of the side-on alkyne nyl halides, Wittig reactions of conjugated alkynals or al- relative to the metal-hydride bond in intermediate C1/2 deter- kynones, and the dehydrations of propargyl alcohols.12–19 The mines the outcome of Pathway C. catalytic dimerization of alkynes to conjugated enynes is a par- Scheme 1. Possible Enyne Products in Alkyne Homo- and ticularly attractive approach owing to its perfect atom economy Cross-Dimerization Reactions and the availability of various alkyne precursors.18–21 However, R R R the homo-dimerization of terminal alkynes may yield the head- cat. R to-tail gem-1,3-enynes and head-to-head E/Z-1,3-enynes 2 R 1,18,19 (Scheme 1). When two different terminal alkynes are used R R as the starting materials, the reaction can potentially give up to E (head-to-tail, gem) (head-to-head, /Z) 12 possible 1,3-enyne products depending on which alkyne acts as the donor (i.e., whose C–C triple bond remains intact) and R1 R2 R1 R2 which acts as the acceptor (i.e., whose C–C triple bond becomes double bond) (Scheme 1).1,18,19 The reaction outcomes could be further complicated by the formations of cumulenes, higher ol- R1 cat. 2 1 1 2 igomers, and polymers.1,18,19 The main challenge in alkyne di- R R R R gem-a gem-b gem-c gem-d merization is how to control the selectivity. R2 1,18,19 The reaction mechanisms have been studied in details R1 R2 R1 R2 and the common reaction pathways are summarized in Scheme 2. Pathway A involves the cleavage of an alkyne C–H bond to form a metal alkynyl intermediate accompanied by deprotona- R2 R1 R1 R2 tion, followed by the side-on coordination of another alkyne E/Z-a E/Z-b E/Z-c E/Z-d molecule to form intermediate A1 or A2; the subsequent inser- In the homo-dimerization of alkynes, the regio- and stereo- tion of a second alkyne into the carbon–metal bond completes selectivity can be controlled by tuning the sterics of the catalyst the carbon framework of the product. Pathway B involves the in general. In the cross-dimerization of two different terminal formation of an alkynyl metal vinylidene species B1 or B2, alkynes, besides the aforementioned types of selectivities, the which may result from the isomerization of A1/A2 via proton chemo-selectivity needs to be controlled as well, i.e., which al- migration; the subsequent insertion of vinylidene into the car- kyne is the donor and which one is the acceptor. Such selectivity bon–metal bond completes the carbon framework of the prod- can be controlled using a few general strategies: (1) one of two uct. In both pathways, the product can then be released from the alkynes has a more reactive C–H bond than the other; (2) one metal center through protonolysis. Pathway C involves the oxi- of the two alkynes is more kinetically retarded to coordinate in dative addition of an alkyne C–H bond onto a low valence metal a side-on fashion as the donor; (3) one of the two alkynes is used center to form C1 or C2, followed by the side-on coordination

in excess to minimize the homo-dimerization of the other. Some Scheme 3. Geminal Selective Dimerization of Terminal Al- of these strategies are often used in synergy to ensure the opti- kynes by the 2-Pyridinolate Borane Complex 1. mal selectivity and overall cross-dimerization performance. R (20 mol %) t During the past few decades, impressive advances have been 1 Bu N O made to develop catalytic systems for the dimerization of al- R B toluene, 100 oC, C F C F kynes with high activity and selectivity as well as functional R 6 5 6 5 1,18,19 6 h group tolerance. Some of these methods have been applied 1 in syntheses of natural products.20–25 Most of the reported selec- up to 93% yield; 100% gem tive alkyne dimerization catalysts are based on noble met- als.1,17,18,26–43 In contrast, catalysts without noble metals are un- BORON derdeveloped. There are some reports on early metal (e.g., In 2018 Gellrich reported a metal-free geminal selective di- Groups 3 and 4 metals as well as f-block elements)44–54 and main merization of terminal alkynes catalyzed by a 2-pyridinolate bo- group catalysts (e.g., Al and Ga)55–57 toward alkyne dimeriza- rane complex 1 (Scheme 3).58 Using a 20 mol % loading of 1 at tion, albeit with relatively limited substrate scopes. In an effort 100 °C, several aryl and aliphatic terminal alkynes were con- to develop sustainable and green alternatives to noble metal cat- verted to the corresponding gem-1,3-enynes with moderate alysts, there has been a recent renaissance in the catalytic alkyne yields within 6 hours. The proposed mechanism is shown in dimerization field. This Perspective Article is focused on the Scheme 4. The dissociation of pyridine from the boron center recent (i.e., after the 2016 review article by Trost and Masters19) of 1 gives 1’, entering the catalytic cycle. The reaction of 1’ advances in the field of catalytic dimerization of alkynes to con- with alkyne generates the 2-pyridinone alkynylborane complex jugated enynes without the use of noble metals. 2, which dissociates into free 2-pyridinone and alkynylborane Scheme 2. Key Steps in Common Reaction Pathways for the 3. The insertion of another alkyne molecule into the B–C(sp) Dimerization of Terminal Alkynes to 1,3-Enynes. The Oxi- bond of 3 gives 4, which is captured by 2-pyridinone to generate dation States of the Metal Centers along Pathway C Are 5. The subsequent protodeborylation releases the gem-1,3- Color Coded in Red. enyne and regenerates 1’. All fundamental steps of the proposed Pathway A catalytic cycle were validated through a series of stoichiometric R R reactions. H+ Scheme 4. Proposed Mechanism for the Dimerization of R [M] [M] - [M] Phenylacetylene Catalyzed by 1. R H [M] R H R 2 R A1 + t - H R R Bu N O + B H C F C F R [M] [M] 6 5 6 5 - [M] 1 H R H R R A2 Pathway B Ph R R R H Ph + H H H Ph H tBu N O [M] • - [M] B R [M] R R C6F5 C6F5 [M] B1 2 R + 1' - H R R R tBu N O H t + Bu N O H H B C F R R 6 5 H R B C6F5 [M] • - [M] C6F5 5 2 C F Ph 6 5 H [M] H Ph B2 Ph Pathway C R R n R t tBu N O Bu N O - [M] Ph H H C6F5 C F (n+2) (n+2) 6 5 Ph B [M] H [M] H B C6F5 C F n R H R 6 5 R H Ph H 3 [M] C1 4 2 R Ph R R n R - [M] IRON (n+2) (n+2) [M] H [M] H Homogeneous iron catalysts are attractive owing to high 59–65 H R R earth-abundance and relatively toxicity of iron. However, H R C2 the development of iron catalysts in the dimerization of terminal alkynes has not received much attention until recent years. Dash and coworkers first reported the use of a sub-stoichiometric 2

amount of FeCl 3 (30 mol %) in the presence of an amine or mol % under the otherwise same conditions, the E:Z selectivity phosphine ligand and 300 mol % of KOtBu towards the dimer- vanished, although a turnover number of 6500 was achieved in ization reactions of aryl acetylenes, which gave the correspond- 4 hours at 120 °C. The variance in selectivity suggests a com- ing 1,3-enynes in moderate to excellent yields within 2 hours at plicated underlying reaction mechanism or multiple reaction 145 °C with the E:Z ratio up to 83:17.66,67 pathways, which are still not well understood. Scheme 5. Fe Complexes as (Pre-)Catalysts towards Dimer- ization of Terminal Alkynes. Huang, Hor, Zhao, and co-workers reported that with a 5 mol t R R R % loading of FeCl2·4H2O and a 300 mol % loading of KO Bu, phenylacetylene can be converted into the corresponding 1,3- Fe (pre-)cat. R 2 R enyne in a 78% yield when heated in a 145 °C oil bath for 2 h 69 R R with the E:Z ratio of 75:25. The use of Fe complexes of pyra- E zole-based tridentate ligands such as complex 7 (Scheme 5) in- (head-to-tail, gem) (head-to-head, /Z) stead of the simple Fe(II) salt under the otherwise same condi- tions gave comparable yields and a slightly higher E:Z ratio N N (80:20). The catalytic reactions could be accelerated by micro- Dipp N Cl wave irradiation, i.e., completion within 10 minutes at 145 °C. N Fe CO Interestingly, the combination of complex 7 and NaOtBu gave OC Fe Cl CO S N N the opposite E/Z selectivity (33:67). For the sterically encum- CO bered (2-methoxyphenyl)acetylene, the combination of com- (0.2 mol %) (5 mol %) t Mandal 2016: 6 Huang, Hor & Zhao 2018: 7 plex 7 and KO Bu displayed no reactivity, whereas the combi- t KOtBu (200 mol %) toluene, 145 °C oil bath, 2 h nation of complex 7 and NaO Bu was able to give good yields toluene, 120 °C, 4 h or 145 °C microwave, 10 min with poor E:Z selectivity. up to 98% yield up to 98% yield t E:Z up to 84:16 KO Bu (300 mol %), E:Z up to 80:20 In 2016 Milstein and coworkers reported a well-defined cata- i CH2 NaOtBu (300 mol %), Z:E up to 70:30 lyst, [Fe(H)(BH4)( Pr-PNP )] 8, towards the Z-selective homo- and cross-dimerization of arylacetylenes in the absence H H 70 i R i of additives at room temperature (Scheme 5). With a 1–3 mol P Pr2 N P Pr2 % loading of the catalyst, a broad scope of arylacetylenes were N Fe H N Fe H2 converted into the corresponding 1,3-enyne products with good P H B H N P iPr R iPr H 2 H 2 to perfect Z selectivity in 12–24 h, where the geminal products (1-3 mol %) (0.2 mol %, Milstein 2016: 8 Kirchner 2018: 9a,b were not obtained. Interestingly, the same catalytic system con- THF, R.T., 12-36 h a, R = H; b, R = Me) verted trimethylsilylacetylene to the corresponding geminal up to 98% yield C6D6, R.T., 0.5-4 h enyne only. On the other hand, aliphatic alkynes and ortho-sub- Z:E up to 98:0 up to 99% yield stituted phenylacetylenes could not be dimerized under the Z:E up to 99:1 standard catalytic conditions. The Z-selective cross-dimeriza- tion was achieved with arylacetylenes as the acceptors and 3 equiv. of trimethylsilylacetylene as the donor. Complex 8 reacts Ph Fe Fe readily with PhC≡C–H and PhC≡C–D to generate a phenyla- N N CH2 Cl cetylide complex [Fe(C≡CPh)(BH4)(PNP )] along with H2 N N and HD, respectively. The lack of deuterium incorporation onto N Mes CH2 − the benzylic position of the P,N,P -ligand or the [BH4] lig- (1-3 mol %) (3-5 mol %) Song 2017: 10 Song 2019: 11 and suggests that the Fe–H is responsible for the alkyne C–H THF, 80 °C, 4-8 h LiHMDS (3-5 mol %) CH2 up to 98% yield toluene, R.T., 0.5-1 h activation. The isolated [Fe(C≡CPh)(BH4)(PNP )] shows 100% gem up to 98% yield comparable catalytic activity with that of 8 under similar reac- 100% gem tion conditions. Neither complex 8 nor CH2 In 2016 Mandal and co-workers reported the dimerization of [Fe(C≡CPh)(BH4)(PNP )] reacts with internal alkynes, sug- aryl acetylenes catalyzed by [Fe(CAAC)(CO)4] 6, where gesting that the Fe–H and Fe–C≡CPh moieties are not prone to CAAC is 1-(2,6-diisopropylphenyl)-2,2,4,4-tetramethyl-pyr- alkyne insertion, at least not for internal alkynes. All these ob- rolidin-5-ylidene (Scheme 5).68 1,3-Enynes were obtained in servations led the authors to propose Pathway B in Scheme 2, moderate to high yields with the E:Z ratio up to 84:16 at a 0.2 involving an Fe–vinylidene intermediate that originates from mol % catalyst loading in the presence of a large excess of the protonation of the phenylacetylide ligand in t CH2 KO Bu (200 mol %) in toluene at 120 °C. A few electron-do- [Fe(C≡CPh)(BH4)(PNP )] by another molecule of terminal nating and electron-withdrawing groups were tolerated by this alkyne. catalytic system. When the aryl group of the substrate was 2- In 2017 Kirchner and coworkers reported the iron complexes methoxylphenyl, 3,5-bis(trifluoromethyl)phenyl, or 2-pyridyl, with two slightly different PNP-pincer ligands, where the link- lower yields of the 1,3-enyne products were observed along ers between the phosphine donors and the central pyridine ring with the opposite selectivity, i.e., more Z than E. When phenyla- are two NH or NMe groups.71,72 While the reactivity of NH cetylene was used as the substrate, the E:Z ratio of the 1,3-enyne [FeH(BH4)(PNP )] complex toward the Z-selective dimeriza- products increases over time under the standard catalytic condi- tion of aryl acetylenes is comparable with that of 8, complexes NH tions. In contrast, when the catalyst loading was lowered to 0.01 [Fe(H) 2(H2)(PNP )] 9a (Scheme 5) and 3

NMe [Fe(H) 2(H2)(PNP )] 9b are significantly more active than 8. vinylidene into the neighboring Fe–C bond gives the pro-Z al- For example, with a 0.2 mol % loading of 9a, several aryl acet- kynyl vinyl complex G. Another alkyne molecule coordinates ylenes were quantitatively converted into the corresponding Z- to form H. The subsequent protonolysis releases the final Z-1,3- 1,3-enynes within 30 minutes at room temperature with Z:E ra- enyne product and regenerates D. The DFT calculations showed tio up to 99:1. This catalytic system is compatible with aryl that the irreversible formations of the pro-Z intermediate G and acetylenes with amino, ester, alkyl, and halide functional its pro-E isomer have comparable energy barriers, i.e., no E/Z groups on the arene ring as well as 3-ethynylthiophene, but dis- selectivity arising from this step. However, the conversion of plays no reactivity towards aliphatic or internal alkynes. The the pro-E isomer to the more stable pro-Z isomer G via a cu- reaction of the electron-rich 4-(dimethylamino)phenylacetylene mulenyl intermediate I (Scheme 7) and the irreversible Z-prod- needs 4 hours to reach completion under the standard reaction uct release are both faster than the E-product release, giving rise conditions. Both 9a and 9b are effective towards the cross-di- to the Z-selectivity. merization of trimethylsilylacetylene and phenylacetylene. In 2017 Song and coworkers reported a well-defined iron(II) Complex 9b showed lower catalytic activities than 9a and was piano-stool complex 10 (Scheme 5) bearing a Cp* and an used to probe the reaction mechanism experimentally and com- N,C,C-chelating ligand for the dimerization of terminal al- putationally. Upon exposure to excess trimethylsilylacetylene, kynes.73 With a 1–3 mol % loading of 10 in THF, both aryl and NMe complex 9b was converted to [Fe(C≡CSiMe3)2(PNP )] (S = aliphatic terminal alkynes can be converted into the correspond- 1) immediately, which can be isolated and characterized crys- ing geminal 1,3-enynes exclusively in good to excellent yields 72 tallographically. With phenylacetylene, the corresponding in 4 hours at 80 °C. A broad range of functional groups can be bis-acetylide complex can be trapped with PMe3 to give a dia- tolerated, including NH and OH substituents. The conversion of NMe magnetic complex [Fe(C≡CPh)2(PNP )(PMe3)]. The bis- the bulky trimethylsilylacetylene is slightly slower. Complex 10 acetylide species was proposed to be an active species in the can also catalyze the cross-dimerization between propargyl al- catalytic cycle. cohol and various aryl acetylenes (Scheme 8a). Using a slight Scheme 6. Proposed Catalytic Cycle for the Dimerization of excess of propargyl alcohol (1.3 eq. with respect to the aryl acet- Terminal Alkynes Catalyzed by 9. ylene), high selectivity for the cross-dimerization product H R N PiPr where propargyl alcohol is the acceptor was achieved. In all 2 cases, only the geminal products were observed. N Fe H2 N P Scheme 7. Proposed (a) Interconversion of pro-Z and pro-E R i H Pr2 Alkylvinyl Species and (b) Cumulenyl Intermediate In- 9 volved. Ar (a) Ph Ph

Me i Me i Ar N P Pr2 Ph N P Pr2 Ph Ar N Fe N Fe

R N PiPr N P N P Ar 2 i i Ar Me Pr2 Me Pr2 N Fe H Ph Ph H N P - - R iPr pro Z pro E Ar 2 Ar Ar D Ar R i R i Ph N P Pr2 N P Pr2 (b) N Fe N Fe Ar H Me i N P N P N P Pr2 R i R i Ph Pr2 Pr2 N Fe H H C Ar N P C Ar H E Me iPr Ar 2 C

Ar H Ph Ar Ar I Me i N P Pr2 Ar R i N P Pr2 To probe the mechanism, complex 10 was reacted with excess N Fe N Fe Ar phenylacetylene.73 Complex 10 and the corresponding phenyla- N P Me iPr N P cetylide complex 13 (in Scheme 9) are the only two observable 2 R iPr C H 2 1 Ar Fe-containing species by H NMR spectroscopy, suggesting H Ar G that they are likely the off-cycle species. The first order depend- F ence of the reaction rate on the alkyne concentration and normal A simplified mechanistic proposal is depicted in Scheme 6.72 secondary KIE (i.e., PhC≡C–H vs PhC≡C–D) led to the mech- Compound 9 reacts with excess terminal alkyne to give bis- anistic proposal shown in Scheme 9.73,74 Initially, the pyridine NR acetylide species [Fe(C≡CAr)2(PNP )] D. An incoming acet- arm in 10 dissociates to produce the 16e species J. The facile ylene molecule coordinates to form a C–H σ complex E, which coordination of an alkyne in an η2 fashion gives intermediate isomerizes into a vinylidene intermediate F. The insertion of the K, followed by the turnover-limiting isomerization to a σ com- plex L. The subsequent σ-bond metathesis produces M, which 4

is in equilibrium with the more stable 18e off-cycle species 13. of a series of piano-stool iron complexes [FeClCp*(NHC)] of Another molecule of alkyne coordinates to form N, followed by monodentate NHC ligands.74 The complex [FeClCp*(IMesBn)] to give complex O. Finally, complex O un- (11, IMesBn = 1-benzyl-3-(2,4,6-trimethylphenyl)-imidazol-2- dergoes another σ-bond metathesis to release the product and ylidene) was found to be a highly active catalyst (Scheme 5). A regenerate the active catalyst J. The orientation of the side-on broad range of alkynes can be converted into the corresponding alkyne in N is crucial for the geminal specificity, i.e., the phenyl geminal 1,3-enynes with 3–5 mol % loadings of 11 and group is pointing away from the bulky NHC ligand. LiHMDS at room temperature in good to excellent yields within To improve the catalytic activity by eliminating the 18e off- 0.5–1 h. Poor to good selectivities were observed in the cross- cycle species, the Song group investigated the catalytic activity dimerization of N,N-dimethylpropargylamine and various ter- minal alkynes catalyzed by 11 (Scheme 8b). Scheme 8. Cross-Dimerization of (a) Aryl Acetylenes and Propargyl Alcohol, and (b) Various Terminal alkynes and N,N- Dimethyl Propargyl Amine. (a) Ar HO Ar HO (3 mol %) 10 Ar + o HO THF, 80 C, 16 h HO Ar Ar HO (1.3 equiv.)

(b) R N R N (5 mol %) 11 LiHMDS (5 mol %) R + N toluene, R.T., 4 h N R R N (2 equiv.) Scheme 9. Proposed Catalytic Cycle for the Dimerization of Phenylacetylene Catalyzed by 10 and 11.

Ph Ar Ph Ar Fe Fe N N H N H N Ph K L

Ar Ar = py Fe Ar = py N Ar Fe Ar = py or Ph Fe Fe Ph N N N N Ph N N Mes N N N J M Mes Ph 10 13

H Ph Ph Ph H Ar Ar Fe N Fe Ph N Ph N H N H Ph Mes Mes O N reported using CoCl2·6H2O/Zn/P–P (P–P = dppe, 1,2-bis(di- COBALT phenylphosphino)-benzene (dppPh), or 2-(2,6-diiso- In some earlier work, several cobalt(I) catalysts were reported propylphenyl)iminomethyl-pyridine) (dipimp)),81 giving differ- for the dimerization of terminal alkynes, such as ent levels of regio-selectivity and stereo-selectivity. The general 75 75,76 75 [CoCl(PPh3)3], [CoCl(PMe3)3], [CoCl(CO)2(PMe3)2], mechanistic proposal involves an of terminal 77 78 [CoH(N 2)(PPh3)3], and [CoCl(PPh3)3]/NaOMe. A few co- alkyne C–H bond onto a low valent cobalt center. Recently, balt (II) compounds were also found active under reducing con- Thomas has reported a Zr/Co bimetallic system as a model of 79 82 ditions (e.g., [Co(acac)2]/PPh3/AlEt3, and [Co- such a process. Br 2(dppe)]/Mg/Zn (dppe = 1,2- bis(diphenylphosphino)- ethane)).80 The cross-dimerization of alkynes using silyl acety- lenes as the donor and internal alkynes as the acceptor was also 5

Scheme 10. Dimerization of Terminal Alkynes Catalyzed by Scheme 11. (a) Sequential Transformation of Aryl Alkynes Co Complex 14. to (E,Z)-1,3-Dienes Catalyzed by 15; (b) Stochiometric Re- (0.5 mol %) Ar Ar action of 15 and Terminal Alkynes. 14 t (a) KO Bu (55 mol %) Ar R (3 mol %) Ar + 15 o (3 mol %) (2 equiv.) PhCl, 60 C, 2 h, Ar 15 H3N•BH3 Ar R o o R up to 83% yield; Z:E up to 93:7 THF, 40 C, 12 h THF, 40 C, 4 h R R up to 98% yield; up to 91% yield E:Z ratio up to 98:0 over two steps N N (b) N Co N

Cl Cl THF or Et2O Co O + Ar Co 14 R. T. Ph P Ph2P N 2 Ar H In 2018 Wang, Sun, and coworkers investigated the catalytic N Ar = Ph, p-MeO-Ph O activity of cobalt(II) complexes of various N-donor chelating 15 ligands toward the dimerization of terminal alkynes, among which complex 14 displayed the best performance.83 Using a 16 0.5 mol % loading of 14 and 55 mol % loading of KOtBu in In 2019 Collins and coworkers reported a photochemical co- chlorobenzene, several aryl acetylene substrates can be con- balt-catalyzed dimerization of terminal alkynes.85 Using verted to E/Z-1,3-enynes in good yields and high Z-selectivity CoBF 4·6H2O (5 mol %), dppp (6 mol %), DIPEA (30 mol %, (i.e., Z:E ratio up to 93:7) in 2 hours at 60 °C under inert atmos- DIPEA = diisopropylethylamine), and a photocatalyst 4CzIPN phere (Scheme 10). No conversion was observed with cyclo- (2 mol %, 4CzIPN = 2,4,5,6-tetra(9-carbazolyl)-isophthaloni- hexylacetylene substrate under the standard reaction conditions. trile) under blue LED irradiation, a variety of aryl acetylenes In 2019 Wang reported the one-pot two-step transformation and cyclohexenyl acetylene can be homo-dimerized into the of aryl acetylenes into E,Z-1,3-dienes catalyzed by phosphino- corresponding E-1,3-enynes in moderate to excellent yields pyridinolate cobalt complex 15, where the first step is the E- (Scheme 12) in 4–18 hours at room temperature with >99:1 E:Z selective alkyne dimerization (Scheme 11).84 Using a 3 mol % ratios. The cross-dimerization reactions between various termi- loading of 15 in THF, various aryl acetylenes with electron-do- nal alkynes as the acceptors and silylacetylenes as the donors nating or electron-withdrawing groups can be dimerized into E- (2.5 equiv.) were also achieved in moderate to excellent yields 1,3-enynes in excellent yields and high selectivity (E:Z ratio up with E-specificity. Additionally, this methodology was also ap- to 98:0) in 12 hours at 40 °C. While no conversion was observed plied to the synthesis of macrocycles under dilute conditions for alkyl acetylenes, trimethylsilylacetylene can be dimerized with a higher catalyst loading. with a lower yield and selectivity (E:Z = 57:19). The subsequent Scheme 12. Photochemical Cobalt-Catalyzed (a) Homo-Di- addition of 2 equiv. of NH3·BH3 smoothly reduces the E-1,3- merization of Terminal Alkynes; (b) Cross-Dimerization of enynes into E,Z-1,3-dienes through cis-addition (Scheme 11a). various Terminal Alkynes; and (c) Macrocyclic Terminal The reaction of 15 with an equimolar amount of ArC≡CH (Ar Alkyne Dimerization. = Ph, p-MeO-Ph) produces the corresponding acetylide com- (a) 4CzIPN (2 mol %) •6H O (5 mol %) plex 16 with a dangling pyridinone moiety (Scheme 11b), re- Co(BF4)2 2 R dppp (6 mol %) sembling the reactivity of the pyridinolate–borane complex pre- DIPEA (30 mol %) 58 viously reported. According to their DFT calculations, the 2 R basic O atom of complex 15 initially deprotonates the alkyne to MeCN [200 mM] Blue LEDs, 18 h R form a cobalt acetylide species, which isomerizes to complex 16 via a barrierless process. The remainder of the mechanistic up to 90% yield; E:Z > 99:1 proposal follows Pathway A in Scheme 2 to give the E-1,3- (b) 4CzIPN (2 mol %) •6H enyne, although the formation of the minor product, Z-1,3- Co(BF4)2 2O (5 mol %) R Si enyne, could not accounted for by this pathway. dppp (6 mol %) 3 DIPEA (30 mol %) + Ar R3Si MeCN [200 mM] (2.5 equiv.) Blue LEDs, 18 h Ar up to 99% yield

4CzIPN (2 mol %) (c) •6H Co(BF4)2 2O (20 mol %) dppp (24 mol %) DIPEA (60 mol %)

MeCN [10 mM] Blue LEDs, 18 h

up to 90% yield; E:Z up to > 99:1

6

Scheme 13. Cross-Dimerization of Terminal Alkynes Cata- Scheme 14. Cross-Dimerization of Terminal Alkynes Cata- lyzed by 17. lyzed by Co(OAc)2 and L2. Trip (a) (3 mol %) R2 (a) 17 R1 •4H O (2.5 mol %) EtMgBr (6 mol %) N Cl Co(OAc)2 (2.52 mol %) 1 + 2 L2 R R Co THF, R.T., 3 h R1 + R2 (1.2 equiv.) Cl o R1 N THF/AcOH, 30 C, 12 h (1.3 equiv.) 2 = aryl or alkyl; R R1 up to > 99% yield = Ar, alkenyl; = Me Trip R1 up to 92% yield R2 Si, tBu MeSi, iPr Si, = alkyl tBu 3 2 3 17 R2 t Bu, (Me3SiO)(Ph)2C P

PPh2 PPh2 L2 (b) Trip Trip EtMgBr (2 equiv.) (b) N Cl N Si 1 1 dvtms (1.5 equiv.) •4H O (5 mol %) R R Co Co Co(OAc)2 (5 mol2 %) O L2 THF, -78o N Cl C - R.T. N Si R1 + + o THF/AcOH, 60 C, 12 h (balloon) Trip Trip = Ar, alkenyl a b 1 up to 14.5:1 17 18 R a: b In 2020, Tsurugi, Mashima, and Ueda described a cobalt-cat- In 2020, Li reported the geminal selective cross-dimerization alyzed highly E-selective cross-dimerization using trimethylsi- of alkynes catalyzed by Co(OAc)2/L2 (L2 = 2,2'-(tert-bu- lylacetylene as the donor and a variety of terminal alkynes as tylphosphinediyl)bis-(2,1-phenylene)bis(diphenylphosphine)), 86 the acceptors (Scheme 13). Using [CoCl2(L1)] 17 (3 mol %, where aryl or alkenyl acetylenes are the donors and a variety of L1 = 2,9-bis(2,4,6-triisopropylphenyl)-1,10-phenanthroline) aliphatic acetylenes are the acceptors (Scheme 14a).87 Using and EtMgBr (6 mol %), a variety of E-1,3-enynes could be syn- Co(OAc)2 (2.5 mol %) and L2 (2.5 mol %) in THF/AcOH, a thesized in excellent yields in 3 hours at room temperature. This variety of gem-1,3-enynes can be synthesized in good to excel- catalytic system is compatible with a broad range of functional lent yields in 12 hours at 30 °C. This catalytic system is com- groups on the acceptor alkynes, such as hydroxy, silylether, ac- patible with broad scopes of both the donor and the acceptor etal, amino, phthalimide, ester, cyano, chloro, thioether, and alkynes. With the gaseous unsubstituted acetylene as the accep- sulfonate. The donor alkyne can also be tertbutylacetylene, or tor alkyne, the catalytic reactions require a higher catalyst load- 1-trimethylsilyloxy-1,1-diphenyl-2-propyne. In the presence of ing and higher temperatures (Scheme 14b). The trimerization a trapping diene ligand divinyltetramethyldisiloxane (dvtms), product 3,5-dien-1-yne (product b in Scheme 14b) was also ob- complex 17 can be reduced with 2 eq. of EtMgBr to a Co(0)- served in small amount, which is likely produced via the initial diene complex [Co(L1)(dvtms)] 18, whose catalytic activity in homo-dimerization of acetylene followed by the cross-dimeri- the absence of EtMgBr is comparable with that of 17 in the pres- zation of the resulting enyne and the donor alkyne. It is interest- ence of EtMgBr. As such, the proposed mechanism involves the ing to point out that the latter step is Z-selective rather than gem- initial reduction of the Co(II) precursor by EtMgBr to an active inal selective, suggesting a different underlying mechanism Co(0) species. The remainder of the mechanistic proposal fol- compared to the mainstream reactions. lows Pathway C in Scheme 2, which is consistent with the deu- The stoichiometric reaction of Co(OAc) 2 and L2 gives terium labeling experiments. DFT calculations comparing tri- [Co(OAc)2(L2)], P, which was characterized by high resolution methylsilylacetylene and propyne show that the active Co(0) ESI-MS. An analogous complex [Co(OBz) 2(L2)] was charac- species selectively reacts with the C–H bond of trimethylsilyla- terized by X-ray crystallography, revealing a 5-coordinate cetylene to form the Co(II) hydride acetylide species. The steric square pyramidal geometry with two monodentate benzoates. A factors prevent homo-dimerization of the donor alkynes as well series of deuterium labeling experiments suggest that the H/D as give rise to the E-selectivity. exchange between the solvent acetic acid and alkynes is fast and the product release is mainly through protonolysis by acetic acid. A proposed mechanism is shown in Scheme 15. One of the acetates in complex P dissociates to form a cationic complex Q, followed by an acetate-assisted C–H activation to form Co(II)–acetylide R and acetic acid. It is conceivable that an al- iphatic acetylene could also react in a similar fashion, however, the acidic solvent is likely keeping the concentration of the re- sulting Co–acetylide intermediate much lower than that of the Co–acetylide intermediate resulting from the more acidic aryl or alkenyl acetylene in the reaction mixture. Such a discrimi- nating solvent is likely ensuring that the more acidic alkyne is the donor. Subsequently, the less bulky aliphatic acetylene (i.e., outcompeting the bulky aromatic or alkenyl acetylenes due to the congestion at the metal center) replaces the acetate ligand in R gives T via intermediate S, followed by migratory insertion and the coordination of acetate anion to form U. Finally, the 7

protonolysis of U by acetic acid releases the enyne product and Scheme 14. KOtBu-Catalyzed (a) Dimerization of Terminal regenerates the catalyst P. The steric congestion at the metal Alkynes and (b) Reaction of Complex 19 with 4-Ethynyltol- center in T also enforces the orientation of the side-on acceptor uene. alkyne and in turn the geminal selectivity. (a) Ar Ar Method A or Scheme 15. Proposed Catalytic Cycle for the Cross-Dimeri- Method B Ar Ar + zation of Terminal Alkynes Catalyzed by Co(OAc)2 and L2. Ar AcO up to 87% yield; E:Z up to 99:1 Ph Ph Ph Ph t P P Method A: KO Bu (7.5 mol %), DMSO, R.T. t o Ph Ph Method B: KO Bu (7.5 mol %), 18-crown-6 (10 mol %), THF, R.T. or 80 C P P t Ph Bu Ph P P tBu Co Co AcO OAc t R1 AcO (b) Bu C p-tolyl P Q O C O O p-tolyl O O H(D) R1 H O K O O K O O O THF, R.T. O O R2 AcOH(D) Ph AcOH Ph 19 20 P Ph Ph Ph The role of the crown ether or DMSO solvent is likely to se- Ph P P tBu P quester the K+, enhancing the basicity of OtBu– for the deproto- H Co Ph OAc Ph P P tBu nation of aryl acetylene as well as improving the reactivity of Co R2 OAc the aryl acetylide anion for the subsequent C–C bond formation 1 R1 R R step. It is conceivable that other suitable ligands may also be U able to sequester K+, effecting catalytic alkyne dimerization re- actions. For example, when a transitional metal complex is used AcO in combination with KOtBu under harsh conditions towards the Ph AcO Ph Ph catalytic dimerization of alkynes, the transition metal complex P Ph R2 H P Ph could potentially decompose to release the free ligand, which P P t Ph + Ph Bu P P t may sequester K and initiate the catalysis without the involve- Co Ph Bu H Co ment of the transition metal in the catalytic cycle. Careful con- R1 R2 R1 trol experiments are needed in order to claim the role of each T S component in the catalytic system. POTASSIUM SUMMARY AND OUTLOOK KOtBu is a commonly used additive in several transition There has been impressive progress on the selective alkyne metal-catalyzed dimerization reactions of terminal alkynes. In dimerization to give 1,3-enynes using catalysts that do not con- 2019, Mandal and coworkers reported the E-selective dimeriza- tain noble metals. Many catalysts have shown high activities tion of terminal alkynes catalyzed by KOtBu in a strongly coor- and excellent functional group tolerance. The challenge in se- dinating solvent, DMSO, or in the presence of 18-crown-6 in lectivity has been tackled through ligand designs. Moreover, the THF (Scheme 14).88 Using a 7.5 mol % loading of KOtBu in concept of cooperative89 catalysis taking advantage of the actor DMSO, a variety of aryl acetylenes bearing electron-donating ligands90 has also been demonstrated in several catalytic sys- or electron-withdrawing groups and 2-pyridyl acetylene can be tems. Although the general mechanistic pathways are well un- dimerized into the corresponding 1,3-enynes in 33–87% yields derstood, the reaction mechanism for each individual catalytic at room temperature with the E:Z ratio up to 99:1. Alternatively, system can still be quite complicated, especially when the par- some of the reactions can be conducted in THF in the presence ticipation of actor ligands are involved, which warrants mecha- of 18-crown-6 with similar selectivity at room temperature or nistic studies on a case-by-case basis. Detailed kinetic analyses, 80 °C. The stoichiometric reaction of the isolated [K(18-crown- isotope labeling experiments, model reactions, and DFT calcu- 6)(OtBu)], 19 with 4-ethynyltoluene produces [K(18-crown- lations are extremely desirable and can contribute to the rational 6)(p-tolylacetylide)], 20, which was characterized by NMR catalyst design. Well-designed control experiments are critical spectroscopy and X-ray crystallography. Both 19 and 20 are especially when additive is used. able to effect the catalytic the dimerization terminal alkynes. Highly selective and widely applicable catalytic systems to- wards the cross-dimerization of alkynes are still relatively rare. Further research work is needed to develop such catalytic sys- tems. Another aspect in this research field that requires further research endeavor is to develop catalytic systems that are robust against various trace impurities in the substrates, including di- oxygen and moisture. Given that 1,3-enynes are widely used in organic syntheses, the use of catalytic alkyne dimerization in cascade reactions warrants extensive investigations and may

8

find many applications in the preparation of complex molecular (15) Deussen, H.-J.; Jeppesen, L.; Schärer, N.; Junager, F.; Bentzen, architectures. B.; Weber, B.; Weil, V.; Mozer, S. J.; Sauerberg, P. Process Develop- ment and Scale-Up of the PPAR Agonist NNC 61−4655. Org. Process AUTHOR INFORMATION Res. Dev. 2004, 8, 363–371. (16) Yan, W.; Ye, X.; Akhmedov, N. G.; Petersen, J. L.; Shi, X. Corresponding Author 1,2,3- Triazole: Unique Ligand in Promoting Iron-Catalyzed Propargyl * E-mail for D.S.: [email protected]. Alcohol Dehydration. Org. Lett. 2012, 14, 2358–2361. (17) Cembellín, S.; Dalton, T.; Pinkert, T.; Schafers, F.; Glorius, F. Author Contributions Highly Selective Synthesis of 1,3-Enynes, Pyrroles, and Furans by Manganese(I)-Catalyzed C−H Activation. ACS Catal. 2020, 10, 197– † Q.L. and K.H. contributed equally. 202. Notes (18) Zhou, Y.; Zhang, Y.; Wang, J. Recent Advances in Transition- Metal-Catalyzed Synthesis of Conjugated Enynes. Org. Biomol. Chem. The authors declare no competing financial interest. 2016, 14, 6638–6650. (19) Trost, B. M.; Masters, J. T. Transition Metal-Catalyzed Cou- ACKNOWLEDGMENT plings of Alkynes to 1,3-Enynes: Modern Methods and Synthetic Ap- We thank Natural Sciences and Engineering Research Council plications. Chem. Soc. Rev. 2016, 45, 2212–2238. (NSERC) of Canada for funding. Q. L. thanks the Ontario govern- (20) Trost, B. M. The Atom Economy–A Search for Synthetic Effi- ment for an Ontario Graduate Scholarship. ciency. Science 1991, 254, 1471–1477. (21) Trost, B. M. Atom Economy–A Challenge for Organic Synthe- REFERENCES sis: Homogeneous Catalysis Leads the Way. Angew. Chem., Int. Ed. Engl. 1995, 34, 259–281. (1) Modern Alkyne Chemistry; Trost, B. M., Li, C.-J., Eds.; Wiley: (20) Trost, B. M.; Yang, H.; Thiel, O. R.; Frontier, A. J.; Brindle, C. Weinheim, Germany, 2015. S. Synthesis of a Ring-Expanded Bryostatin Analogue. J. Am. Chem. (2) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei, I. A.; Tang, Soc. 2007, 129, 2206–2207. W. Enantioselective Bromolactonization of Conjugated (Z)-Enynes. J. (21) Trost, B. M.; Yang, H.; Dong, G. Total Syntheses of Bry- Am. Chem. Soc. 2010, 132, 3664–3665. ostatins: Synthesis of Two Ring‐Expanded Bryostatin Analogues and (3) Kong, J.-R.; Ngai, M.-Y.; Krische, M. J. Highly Enantioselective the Development of a New‐Generation Strategy to Access the C7– Direct Reductive Coupling of Conjugated Alkynes and α-Ketoesters C27 Fragment. Chem.-Eur. J. 2011, 17, 9789–9805. via Rhodium-Catalyzed Asymmetric Hydrogenation. J. Am. Chem. (22) Trost, B. M.; Yang, H.; Brindle, C. S.; Dong, G. Atom‐Eco- Soc. 2006, 128, 718–719. (4) Wessig, P.; Müller, G. The Dehydro-Diels−Alder Reaction. nomic and Stereoselective Syntheses of the Ring A and B Subunits of Chem. Rev. 2008, 108, 2051–2063. the Bryostatins. Chem.-Eur. J. 2011, 17, 9777–9788. (5) Barday, M.; Ho, K. Y. T.; Halsall, C. T.; Aïssa, C. Regioselective (23) Trost, B. M.; Yang, H.; Wuitschik, G. A Ru-Catalyzed Tandem Synthesis of 3-Hydroxy-4,5-alkyl-Substituted Pyridines Using 1,3- Alkyne−Enone Coupling/Michael Addition: Synthesis of 4-Meth- Enynes as Alkynes Surrogates. Org. Lett. 2016, 18, 1756–1759. ylene-2,6-cis-tetrahydropyrans. Org. Lett. 2005, 7, 4761–4764. (6) Kumar, R.; Tamai, E.; Ohnishi, A.; Nishimura, A.; Hoshimoto, (24) Trost, B. M.; Dong, G. Total Synthesis of Bryostatin 16 using Y.; Ohashi, M.; Ogoshi, S. Nickel-Catalyzed Enantioselective Synthe- Atom-economical and Chemoselective Approaches. Nature 2008, 456, sis of Cyclobutenes via [2 + 2] Cycloaddition of α,β- Unsaturated Car- 485–488. bonyls with 1,3-Enynes. Synthesis 2016, 48, 2789–2794. (25) Trost, B. M.; Dong, G. Total Synthesis of Bryostatin 16 Using (7) Zhou, X.; Huang, C.; Zeng, Y.; Xiong, J.; Xiao, Y.; Zhang, J. a Pd-Catalyzed Diyne Coupling as Macrocyclization Method and Syn- Silver-Catalysed Tandem Hydroamination and Cyclization of 2-Tri- thesis of C20-epi-Bryostatin 7 as a Potent Anticancer Agent. J. Am. fluoromethyl-1,3-enynes with Primary Amines: Modular Entry to 4- Chem. Soc. 2010, 132, 16403–16416. Trifluoromethyl-3-pyrrolines. Chem. Commun. 2017, 53, 1084–1087. (26) Yi, C. S.; Liu, N. Homogeneous Catalytic Dimerization of Ter- (8) Campbell, K.; Kuehl, C. J.; Ferguson, M. J.; Stang, P. J.; Tykwin- minal Alkynes by C 5Me5 Ru(L)H3 (L = PPh3, PCy3, PMe3). Organo- ski, R. R. Coordination-Driven Self-Assembly: Solids with Bidirec- metallics 1996, 15, 3968–3971. tional Porosity. J. Am. Chem. Soc. 2002, 124, 7266–7267. (27) Yi, C. S.; Liu, N. The Ruthenium Acetylide Catalyzed Cross- (9) Nicolaou, K. C.; Dai, M. W.; Tsay, S. C.; Estevez, V. A.; Wrasi- Coupling Reaction of Terminal and Internal Alkynes: Isolation of a dlo, W. Designed Enediynes: A New Class of DNA-Cleaving Mole- Catalytically Active β-Agostic Intermediate Species. Organometallics cules with Potent and Selective Anticancer Activity. Science 1992, 256, 1998, 17, 3158–3160. 1172–1178. (28) Ogata, K.; Toyota, A. Iridium(I) Complex of Chelating Pyri- (10) Goldberg, I. H. Mechanism of Neocarzinostatin Action: Role of dine-2-thiolate Ligand: Synthesis, Reactivity, and Application to the DNA Microstructure in Determination of Chemistry of Bistranded Ox- Catalytic E-Selective Terminal Alkyne Dimerization via C−H Activa- idative Damage. Acc. Chem. Res. 1991, 24, 191–198. tion. J. Organomet. Chem. 2007, 692, 4139–4146. (11) Kim, H.; Lee, H.; Lee, D.; Kim, S.; Kim, D. Asymmetric Total (29) Conifer, C.; Gunanathan, C.; Rinesch, T.; Hçlscher, M.; Leitner, Syntheses of (+)-3-(Z)-Laureatin and (+)-3-(Z)-Isolaureatin by “Lone W. Solvent-Free Hydrosilylation of Terminal Alkynes by Reaction Pair−Lone Pair Interaction-Controlled” Isomerization. J. Am. Chem. with a Nonclassical Ruthenium Hydride Pincer Complex. Eur. J. Inorg. Soc. 2007, 129, 2269–2274. Chem. 2015, 2015, 333–339. (12) Negishi, E.; Anastasia, L. Palladium-Catalyzed Alkynylation. (30) Powała, B.; Pietraszuk, C. Regio- and Stereoselective Homodi- merization of Monosubstituted Acetylenes in the Presence of the Sec- Chem. Rev. 2003, 103, 1979–2018. (13) Chinchilla, R.; Nájera, C. The Sonogashira Reaction: A Boom- ond Generation Grubbs Catalyst. Catal. Lett. 2014, 144, 413–418. ing Methodology in Synthetic Organic Chemistry. Chem. Rev. 2007, (31) Kawata, A.; Kuninobu, V.; Takai, K. Rhenium-Catalyzed Re- 107, 874–922. gioand Stereoselective Dimerization and Cyclotrimerization of Termi- (14) Ranu, B. C.; Adak, L.; Chattopadhay, K. Hydroxyapatite- Sup- nal Alkynes. Chem. Lett. 2009, 38, 836–837. ported Palladium-Catalyzed Efficient Synthesis of (E)-2--4- (32) Bassetti, M.; Pasquini, C.; Raneri, A.; Rosato, D. Selective Di- ynecarboxylic Esters. Intense Fluorescence Emission of Selected Com- merization of Arylalkynes to (E)-1,4-Diaryl Enynes Catalyzed by the pounds. J. Org. Chem. 2008, 73, 5609–5612. [Ru(p-cymene)Cl2] 2/Acetic Acid System under Phosphine-Free Con- ditions. J. Org. Chem. 2007, 72, 4558–4561. 9

(33) Hijazi, A.; Parkhomenko, K.; Djukic, J.-P.; Chemmi, A.; Pfef- (50) Akita, M.; Yasuda, H.; Nakamura, A. Regioselective Homo- fer, M. Head-to-Head Homo-Coupling of Arylethynes Catalysed by and Codimerization of 1-Alkynes Leading to 2,4-Disubstituted 1-Bu- 5 (Dicarbonyl)ruthenium Chloride Metallacycles: Selective Synthesis of ten-3-ynes by Catalysis of a (η -C5Me5) 2TiCl2 /RMgX System. Bull. (E)-1,4-Diarylbut-1-en-3-ynes. Adv. Synth. Catal., 2008, 350, 1493– Chem. Soc. Jpn. 1984, 57, 480–487. 1496. (51) Platel, R. H.; Schafer, L. L. Zirconium Catalyzed Alkyne Di- (34) Ostrowska, S.; Szymaszek, N.; Pietraszuk, C. Selective Dimer- merization for Selective Z-Enyne Synthesis. Chem. Commun. 2012, 48, ization of Terminal Acetylenes in the Presence of PEPPSI Precatalysts 10609–10611. and Relative Chloro- and Hydroxo-Bridged N-Heterocyclic Carbene (52) Nishiura, M.; Hou, Z.; Wakatsuki, Y.; Yamaki, T.; Miyamoto, Palladium Dimers. J. Organomet. Chem. 2018, 856, 63–69. T. Novel Z-Selective Head-to-Head Dimerization of Terminal Alkynes (35) Ogata, K.; Oka, O.; Toyota, A.; Suzuki, N.; Fukuzawa, S.-i. Catalyzed by Lanthanide Half-Metallocene Complexes. J. Am. Chem. Phosphine-Dependent Selective Cross-Dimerization between Terminal Soc. 2003, 125, 1184–1185. Alkylacetylene and Silylacetylene by Iridium(I) Guanidinate Complex- (53) Komeyama, K.; Kawabata, T.; Takehira, K.; Takaki, K. Rare- Phosphine System. Synlett 2008, 2008, 2663–2666. Earth Silylamide-Catalyzed Selective Dimerization of Terminal Al- (36) Katagiri, T.; Tsurugi, H.; Satoh, T.; Miura, M. Rhodium-cata- kynes and Subsequent Hydrophosphination in One Pot. J. Org. Chem. lyzed (E)-Selective Cross-Dimerization of Terminal Alkynes. Chem. 2005, 70, 7260–7266. Commun. 2008, 3405–3407. (54) Ge, S.; Norambuena, V. F. Q.; Hessen, B. Highly Efficient Re- (37) Azpíroz, R.; Rubio-Pérez, L.; Castarlenas, R.; Pérez-Torrente, gio- and Stereoselective Dimerization of (Hetero)aromatic Terminal J. J.; Oro, L. A. gem-Selective Cross-Dimerization and Cross-Trimeri- Alkynes by Organo Rare-Earth Metal Catalysts. Organometallics zation of Alkynes with Silylacetylenes Promoted by a Rhodium−Pyri- 2007, 26, 6508–6510. dine−N-Heterocyclic Carbene Catalyst. ChemCatChem 2014, 6, 2587– (55) Korolev, A. V.; Guzei, I. A.; Jordan, R. F. Reactivity of Cati- 2592. onic Organoaluminum Aminotroponiminate Compounds with Unsatu- (38) Ogoshi, S.; Ueta, M.; Oka, M.; Kurosawa, H. Dimerization of rated Substrates. Formation of Dinuclear Dicationic Aluminum Com- Terminal Alkynes Catalyzed by a Nickel Complex Having a Bulky plexes. J. Am. Chem. Soc. 1999, 121, 11605–11606. Phosphine Ligand. Chem. Commun. 2004, 2732–2733. (56) Dash, A. K.; Eisen, M. S. Chemo- and Regioselective Dimeri- (39) Katayama, H.; Yari, H.; Tanaka, M.; Ozawa, F. (Z)-Selective zation of Terminal Alkynes Promoted by Methylaluminoxane. Org. Cross-Dimerization of Arylacetylenes with Silylacetylenes Catalyzed Lett. 2000, 2, 737–740. by Vinylideneruthenium Complexes. Chem. Commun. 2005, 4336– (57) Yamaguchi, M.; Hayashi, A.; Hirama, M. Alkynyldichlorogal- 4338. liums are Unstable in Hydrocarbon Solvents Dimerization of Al- (40) Żak, P.; Bołt, M.; Lorkowski, J.; Kubicki, M.; Pietraszuk, C. kynyldichlorogalliums via Carbogallation. Chem. Lett. 1995, 24, 1093– Platinum Complexes Bearing Bulky N-Heterocyclic Carbene Ligands 1094. as Efficient Catalysts for the Fully Selective Dimerization of Terminal (58) Hasenbeck, M.; Müller, T.; Gellrich, U. Metal-free gem Selec- Alkynes. ChemCatChem 2017, 9, 3627–3631. tive Dimerization of Terminal Alkynes Catalyzed by a Pyridonate Bo- (41) Kleinhans, G.; Guisado-Barrios, G.; Liles, D. C.; Bertrand, G.; rane Complex. Catal. Sci. Technol. 2019, 9, 2438–2444. Bezuidenhout, D. I. A rhodium(I)–oxygen adduct as a selective catalyst (59) Egorova, K. S.; Ananikov, V. P. Which Metals are Green for for one-pot sequential alkyne dimerization-hydrothiolation tandem re- Catalysis? Comparison of the Toxicities of Ni, Cu, Fe, Pd, Pt, Rh, and actions. Chem. Commun, 2016, 52, 3504–3507. Au Salts. Angew. Chem., Int. Ed. 2016, 55, 12150–12162. (42) Storey, C. M.; Kalpokas, A.; Gyton, M. R.; Kramer, T.; Chap- (60) Bauer, I.; Knölker, H.-J. Iron Catalysis in Organic Synthesis. lin, A. B. A Shape Changing Tandem Rh(CNC) Catalyst: Preparation Chem. Rev. 2015, 115, 3170–3387. of Bicyclo[4.2.0]octa-1,5,7-trienes from Terminal Aryl Alkynes. (61) Iron Catalysis. Fundamentals and Applications, Plietker B. Ed., Chem. Sci. 2020, 11, 2051–2057. Topics in , Springer, Heidelberg, 2011, vol. (43) Storey, C. M.; Gyton, M. R.; Andrew, R. E.; Chaplin, A. B. 33. Terminal Alkyne Coupling Reactions through a Ring: Mechanistic In- (62) Fürstner, A. Iron Catalysis in Organic Synthesis: A Critical As- sights and Regiochemical Switching. Angew. Chem., Int. Ed. 2018, 57, sessment of What It Takes To Make This Base Metal a Multitasking 12003–12006. Champion. ACS Cent. Sci. 2016, 2, 778–789. (44) Oshovsky, G. V.; Hessen, B.; Reek, J. N. H.; de Bruin, B. Elec- (63) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Direct C–H Transformation via tronic Selectivity Tuning in Titanium(III)-Catalyzed Acetylene Cross- Iron Catalysis. Chem. Rev., 2011, 111, 1293–1314. Dimerization Reactions. Organometallics 2011, 30, 6067–6070. (64) Shang, R.; Ilies, L.; Nakamura, E. Iron-Catalyzed C–H Bond (45) den Haan, K. H.; Wielstra, Y.; Teuben, J. H. Reactions of Yt- Activation. Chem. Rev. 2017, 117, 9086–9139. trium-Carbon Bonds with Active Hydrogen-Containing Molecules. A (65) Liang, Q.; Song D. Iron N-Heterocyclic Carbene Complexes in Useful Synthetic Method for Permethylyttrocene Derivatives. Organo- Homogeneous Catalysis. Chem. Soc. Rev., 2020, 49, 1209–1232. metallics 1987, 6, 2053–2060. (66) Midya, G. C.; Paladhi, S.; Dhara, K.; Dash, J. Iron Catalyzed (46) Heeres, H. J.; Teuben, J. H. Catalytic Oligomerization of Ter- Highly Regioselective Dimerization of Terminal Aryl Alkynes. Chem. 5 minal Alkynes by Lanthanide Carbyls (η -C5Me5) 2LnCH(SiMe 3)2 Commun. 2011, 47, 6698–6700. (Ln = Y, La, Ce). Organometallics 1991, 10, 1980–1986. (67) Midya, G. C.; Parasar, B.; Dhara, K.; Dash, J. Ligand Mediated (47) Horton, A. D. Unprecedented Isolation of Alk-1-en-3-yn-1-yl Iron Catalyzed Dimerization of Terminal Aryl Alkynes: Scope and Intermediates in the Catalytic Oligomerisation of Alk-1-ynes by Cati- Limitations. Org. Biomol. Chem. 2014, 12, 1812–1822. onic Lewis Base-Free Zirconocene Complexes. J. Chem. Soc., Chem. (68) Bhunia, M.; Sahoo, S. R.; Vijaykumar, G.; Adhikari, D.; Man- Commun. 1992, 185–187. dal, S. K. Cyclic (Alkyl)amino Carbene Based Iron Catalyst for Regi- (48) Horáček, M.; Štĕpnička, P.; Kubišta, J.; Gyepes, R.; Mach, K. oselective Dimerization of Terminal Arylalkynes. Organometallics Reactions of Substituted Zirconocene−Bis(trimethylsilyl)ethyne Com- 2016, 35, 3775–3780. plexes with Terminal Alkynes. Organometallics 2004, 23, 3388–3397. (69) Xue, F.; Song, X.; Lin, T. T.; Munkerup, K.; Albawardi, S. F.; (49) Yoshida, M.; Jordan, R. F. Catalytic Dimerization of Terminal Huang, K.-W.; Hor, T. S. A.; Zhao, J. Dimerization of Terminal Aryl Alkynes by a Hafnium Carboranyl Complex. A “Self-Correcting” Cat- Alkynes Catalyzed by Iron(II) Amine-Pyrazolyl Tripodal Complexes alyst. Organometallics 1997, 16, 4508–4510. with E/Z Selectivity Controlled by tert-Butoxide. ACS Omega 2018, 3, 5071–5077.

10

(70) Rivada-Wheelaghan, O.; Chakraborty, S.; Shimon, L. J. W.; [2+2+2]-Cyclotrimerisation Versus Diels–Alder Reaction Versus Ben-David, Y.; Milstein, D. Z-Selective (Cross-)Dimerization of Ter- [4+2+2]-Cycloaddition. J. Organomet. Chem. 2005, 690, 5170–5181. minal Alkynes Catalyzed by an Iron Complex. Angew. Chem., Int. Ed. (81) Sakurada, T.; Sugiyama, Y.-K.; Okamoto, S. Cobalt-Catalyzed 2016, 55, 6942–6945. Cross Addition of Silylacetylenes to Internal Alkynes. J. Org. Chem. (71) Gorgas, N.; Alves, L. G.; Stöger, B.; Martins, A. M.; Veiros, L. 2013, 78, 3583–3591. F.; Kirchner, K. Stable, Yet Highly Reactive Nonclassical Iron(II) Pol- (82) Beattie, J. W.; Wang, C.; Zhang, H.; Krogman, J. P.; Foxman, yhydride Pincer Complexes: Z-Selective Dimerization and Hydrobora- B. M.; Thomas, C. M. Dimerization of Terminal Alkynes Promoted by tion of Terminal Alkynes. J. Am. Chem. Soc. 2017, 139, 8130–8133. a Heterobimetallic Zr/Co Complex. Dalton Trans. 2020, 49, 2407– (72) Gorgas, N.; Stöger, B.; Veiros, L. F.; Kirchner, K. Iron(II) 2411. Bis(acetylide) Complexes as Key Intermediates in the Catalytic Hydro- (83) Xu, D.; Sun, Q.; Quan, Z.; Wang, C.; Sun, W. Cobalt-Catalyzed functionalization of Terminal Alkynes. ACS Catal. 2018, 8, 7973– Dimerization and Homocoupling of Terminal Alkynes. Asian J. Org. 7982. Chem. 2018, 7, 155–159. (73) Liang, Q.; Osten, K. M.; Song, D. Iron-Catalyzed gem-Specific (84) Zhuang, X.; Chen, J.-Y.; Yang, Z.; Jia, M.; Wu, C.; Liao, R.- Dimerization of Terminal Alkynes. Angew. Chem., Int. Ed. 2017, 56, Z.; Tung, C.-H.; Wang, W. Sequential Transformation of Terminal Al- 6317–6320. kynes to 1,3-Dienes by a Cooperative Cobalt Pyridonate Catalyst. Or- (74) Liang, Q.; Sheng, K.; Salmon, A.; Zhou, V. Y.; Song, D. Active ganometallics 2019, 38, 3752–3759. Iron(II) Catalysts toward gem-Specific Dimerization of Terminal Al- (85) Grenier-Petel, J.-C.; Collins, S. K. Photochemical Cobalt-Cata- kynes. ACS Catal. 2019, 9, 810–818. lyzed Hydroalkynylation To Form 1,3-Enynes. ACS Catal. 2019, 9, (75) Field, L. D.; Ward, A. J. Catalytic Hydrosilylation of Acety- 3213−3218. lenes Mediated by Phosphine Complexes of Cobalt(I), Rhodium(I), and (86) Ueda, Y.; Tsurugi, H.; Mashima K. Cobalt-Catalyzed (E)-Se- Iridium(I). J. Organomet. Chem. 2003, 681, 91–97. lective Cross-Dimerization of Terminal Alkynes via a Mechanism In- (76) Field, L. D.; Ward, A. J.; Turner, P. The Dimerization and Cy- volving Co(0/II) Redox Cycles. Angew. Chem., Int. Ed. 2020, 59, clotrimerization of Acetylenes Mediated by Phosphine Complexes of 1552−1556. Cobalt(I), Rhodium(I), and Iridium(I). Aust. J. Chem. 1999, 52, 1085– (87) Chen, J.-F.; Li, C. Cobalt-Catalyzed gem-Cross-Dimerization 1092. of Terminal Alkynes. ACS Catal., 2020, 10, 3881–3889. (77) Herrmann, R.; Pombeiro, A. J. L. Activation of Alkynes by the (88) Ahmed, J.; Swain, A. K.; Das, A.; Govindarajan, R.; Bhunia, Dinitrogen Complex [CoH(N2)(PPh3)3] Towards Catalytic Oligomer- M.; Mandal, S. K. A K-Arylacetylide Complex for Catalytic Terminal ization and Cyclization Reactions. Monatsh. Chem. 1988, 119, 583– Alkyne Functionalization Using KOtBu as a Precatalyst. Chem. Com- 589. mun. 2019, 55, 13860–13863. (78) Rhyoo, H. Y.; Lee, B. Y.; Yu, H. K. B.; Chung, Y. K. Study of (89) Khusnutdinova, J. R.; Milstein, D. Metal–Ligand Cooperation. the Reactivity of ClCo(PPh 3) 3. J. Mol. Catal. 1994, 92, 41–49. Angew. Chem., Int. Ed., 2015, 54, 12236–12273. (79) Dzhemilev, U. M.; Khusnutdinov, R. I.; Shchadneva, N. A.; (90) Annibale, V. T.; Song, D. Multidentate Actor Ligands as Ver- Nefedov, O. M.; Tolstikov, G. A. Some New Transformations of Cy- satile Platforms for Small Molecule Activation and Catalysis. RSC Adv. clopropylacetylene Catalyzed by Rhodium, Palladium, and Cobalt 2013, 3, 11432–11449. Complexes. Russ. Chem. Bull. 1989, 38, 2171–2174. (80) Hilt, G.; Hess, W.; Vogler, T.; Hengst, C. Ligand and Solvent Effects on Cobalt(I)-Catalysed Reactions: Alkyne Dimerisation Versus

11

Graphic TOC

Recent development of catalytic alkyne dimerization without using noble metals: mechanism and prospects.

12