FEATURE ARTICLE www.rsc.org/chemcomm | ChemComm Alkyne metathesis Alois Fu¨rstner* and Paul W. Davies Received (in Cambridge, UK) 22nd December 2004, Accepted 27th January 2005 First published as an Advance Article on the web 28th February 2005 DOI: 10.1039/b419143a This review discusses the emergence of alkyne metathesis as a valuable synthetic tool applicable in the synthesis of complex molecules and polymer science. Introduction proposed as early as 1975 that metal carbynes likely account for the catalytic turnover5 in a sequence of formal [2+2] A striking success in the catalytic arena is alkene metathesis cycloaddition and cycloreversion steps as depicted in Scheme 2. which has been rapidly incorporated into the synthetic lexicon, Even though at the time of this proposal the known metal now existing as one of the primary tools considered in both carbyne complexes were unable to induce alkyne metathesis organic synthesis and polymer chemistry. This is due to the reactions,6 this mechanism was later experimentally estab- extraordinary generality, chemoselectivity, functional group lished by Schrock using high valent metal alkylidynes.7 tolerance and predictability associated with the method. These Several metallacyclobutadiene complexes formed by the [2+2] factors, coupled with the ready availability of the catalysts, cycloaddition of alkylidynes and alkynes were isolated and have fuelled the widespread use of alkene metathesis in many characterised8 and proven to be catalytically competent synthetic routes.1 intermediates. In comparison, the related metathesis of alkynes is in its The ‘‘Mortreux systems’’ have gained relatively widespread infancy.2 Only recently has it been shown that this transforma- use due to their ease of application; cheap, commercially tion holds great synthetic promise. This feature article is intended as an entry point charting the recent developments in this emerging field rather than as a comprehensive review. Classical catalyst systems for alkyne metathesis Alkyne metathesis refers to the mutual exchange of the alkylidyne units between a pair of (non-terminal) acetylene derivatives. The first effective catalyst described in the literature consists of a heterogeneous mixture of tungsten oxides and silica that operates only at a very high temperature (ca. 200–450 uC) and is therefore hardly relevant for preparative purposes.3 This disclosure was followed by the work of Mortreux et al. showing that such a scrambling Scheme 1 Mortreux’s discovery. process is effected by a homogeneous mixture of Mo(CO)6 (or related molybdenum sources) and simple phenol additives heated in high boiling solvents (Scheme 1).4 Whilst the nature of the catalytically active species formed in situ from these precursors remained elusive, Katz et al. *[email protected] Scheme 2 Accepted mechanism of alkyne metathesis. Alois Fu¨rstner (1962) studied chemistry at the Technical of the ACS (2002), the Centenary Lectureship of the RSC University of Graz, Austria, where he got his PhD in 1987 (2003), the Tetrahedron Chair (2004), as well as industrial (Professor H. Weidmann). After postdoctoral studies with the awards from Merck and AstraZeneca. late Professor W. Oppolzer in Geneva, he finished his Habilitation in Graz (1992) before joining the Max-Planck- Paul Davies (1977) studied chemistry at the University of Institut fu¨r Kohlenforschung, Mu¨lheim, Germany, in 1993 as a Sheffield, UK, receiving his MChem degree in 1999. He was group leader. Since 1998, he has been Director at that Institute awarded his PhD in 2003 from the University of Bristol where he and is also affiliated with the University of Dortmund. He has worked with Professor Varinder K. Aggarwal in the area of received several awards for his work on organometallic palladium catalysis. Since 2003 he has been a post-doctoral co- chemistry, homogeneous catalysis, and natural product synthesis worker with Professor Fu¨rstner in Mu¨lheim exploring the including the prestigious Leibniz award from the German Science development of new catalysts for metathesis processes whilst Foundation (1999), the IUPAC-Thieme Prize in Synthetic continuing to pursue his interests in the development of new Organic Chemistry (2000), the Arthur C. Cope Scholar Award transition metal-catalysed transformations. This journal is ß The Royal Society of Chemistry 2005 Chem. Commun., 2005, 2307–2320 | 2307 available and stable ‘‘off the shelf’’ reagents can be used without the requirement for rigorously purified solvents and inert atmosphere. Whilst these factors make this an attractive protocol from a practical point of view, with growing applications in polymer chemistry (vide infra), the rather harsh conditions required and the low activity preclude its use with sensitive moieties. Scheme 4 Scaleable preparation of the tungsten alkylidyne complex 1. To address these issues approaches such as purging the reaction mixture with dinitrogen to remove the released by- afford cyclic alkynes. While early reports of alkyne metathesis product,9 temperature adjustment and the addition of chelat- dealt only with the dimerisation or cross metathesis of simple ing 1,2-diphenyloxyethane10 have resulted in somewhat higher acetylene derivatives7,12a,16,23 and specialty polymers24 (vide yields and reaction rates. System pre-activation by heating the infra), we were able to show the efficient syntheses of phenol and molybdenum species either with11 or without10 functionalised macrocycles by ring closing alkyne metathesis sacrificial 3-hexyne prior to addition of the desired reaction (RCAM).25 This report utilised tungsten alkylidyne 1 under partners resulted in extension of the scope and the use of lower high dilution in either trichlorobenzene, chlorobenzene, temperatures, respectively. toluene or THF. The removal of butyne or hexyne side Recent reports by Grela et al. emphasise the beneficial products under vacuum was found to be beneficial for effects of certain phenols and integrate their use with the conversion in some cases. Whilst terminal alkynes were known approaches mentioned above. Building on Mori’s12 and later to be incompatible with the catalyst6b,21b–c end-capped Bunz’s9,13 advances, Grela identified 2-fluorophenol and substrates with R 5 Me or Et were successfully transformed. 2-fluoro-5-methylphenol as the optimal additives in various This initial report highlighted the lack of any formation of 14 alkyne metatheses. unwanted allenic by-products associated with preparation of cycloalkynes via conventional methods and demonstrated that Well-defined precatalysts for alkyne metathesis cyclic products with ring sizes 12 or greater can be obtained in good to excellent yields.25 Although no ‘‘Fischer-type’’ carbyne has been found that Ether, ester, enoate, amide, silyl ether, sulfonamide, allows alkyne metathesis to proceed to any sustained degree, carbamate and sulfone functionalities were accommodated in Schrock et al. have demonstrated in a series of elegant the RCAM process catalysed by complex 1 (Table 1).26 investigations that the corresponding high valent metal alkylidyne complexes are catalytically competent and remark- Table 1 Formation of cycloalkynes by RCAM: comparison of the ably active (Scheme 3).15 performance of the tungsten alkylidyne catalyst 1 with the Mortreux catalyst system (‘instant’ activation of Mo(CO) with p-ClC H OH) Strikingly, they were found to be unreactive towards alkenes16 6 6 4 suggesting that metal alkylidyne complexes allow orthogonal Yield (%) activation of unsaturated C–C bonds despite the obvious Product Complex 1 ‘Instant’ mechanistic ties between alkene and alkyne metathesis.17 Most applications involving Schrock alkylidyne complexes 73 64 18 utilise (tBuO)3WMCCMe3 1 and related species which operate under fairly mild conditions, sometimes ambient temperature, effecting up to several hundred catalytic turnovers per minute. 52 Preparation of 1 via the metathetic event between 19 (tBuO)3WMW(OtBu)3 and neoheptyne (Scheme 4) is the most convenient approach amenable to be carried out on a fairly large scale;15 importantly, complex 1 has recently been made 20 62 (R 5 H) 0(R5 H) commercially available. As there have been several recent 72 (R 5 Me) 64 (R 5 Me) reviews on the preparation and properties of metal alkylidynes, their background will not be discussed here any further.6b,15,21 Ring closing alkyne metathesis (RCAM) 62 68 Evolving from our interest in Ring Closing Metathesis (RCM) for macrocycle formation22 we investigated the potential for alkyne metathesis to realise the ring closing of acyclic diynes to 55 decomp. Scheme 3 Early demonstration of the exceptional activity of defined alkylidyne complexes as catalysts for alkyne metathesis. 2308 | Chem. Commun., 2005, 2307–2320 This journal is ß The Royal Society of Chemistry 2005 Similarly cycloalkyne 3 containing a meta-pyronophane skeleton could be prepared in high yields using this procedure during a model study towards bioactive pyrone derivatives (Scheme 5).27 Limitations were encountered with functional groups evincing high affinity to the Lewis acidic tungsten centre of complex 1 such as thioether or basic nitrogen groups which were recovered unchanged. Likewise, a butynoate failed to afford the desired product. Comparison of different tungsten alkylidyne complexes showed there to be no major improvement in terms of yield or reaction rate by choosing either different alkylidyne substituents or by replacing the tert- butoxy ligands in 1 with more electron withdrawing hexa- fluoro-2-propoxy