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 Catalysis, 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 Chemistry, 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 2 R 4 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.