This report concerns the development of an efficient Sonogashira-type coupling of arylmethylsulfides and terminal alkynes to generate aryl alkyne motifs. Orthogonal reactivity between traditional Pd catalysts, and the Rh catalysts employed, results in the ability to selectively activate either the C–S bond or C–X bond through catalyst choice. The Rh–bisphosphine catalyst has further been shown to be able to effect a hydroacylation-Sonogashira tandem sequence, and in combination with further onward reactions has been used in the synthesis of heterocycles and polycyclic systems

Arambasic, M

Majhail, M

Neuhaus, J

Straker, R

Willis, M

Arambasic, Milan

Majhail, Manjeet

Straker, Robert

Neuhaus, James

Willis, Michael

Oxford University Research Archive

This journal is©The Royal Society of Chemistry 2019 Chem. Commun.Cite this:DOI: 10.1039/c9cc00092eA rhodium-catalysed Sonogashira-type couplingexploiting C–S functionalisation: orthogonalitywith palladium-catalysed variants†Milan Arambasic, Manjeet K. Majhail, Robert N. Straker, James D. Neuhaus andMichael C. Willis *This report concerns the development of an efficient Sonogashira-type coupling of arylmethylsulfides and terminal alkynes to generatearyl alkyne motifs. Orthogonal reactivity between traditional Pdcatalysts, and the Rh catalysts employed, results in the ability toselectively activate either the C–S bond or C–X bond throughcatalyst choice. The Rh–bisphosphine catalyst has further beenshown to be able to effect a hydroacylation-Sonogashira tandemsequence, and in combination with further onward reactions hasbeen used in the synthesis of heterocycles and polycyclic systems.Since its discovery in 1975 by the laboratories of Cassar, Heckand Sonogashira,1 the coupling of aryl halides with terminalalkynes has represented one of the most popular methodsof assembling aryl alkynes.2 The prototypical ‘‘Sonogashiracoupling’’ revolves around the co-operative action of a Pd-catalystwith a Cu-co-catalyst, used to activate the terminal alkyne.Synthetically straightforward, the reaction has been the subjectof countless studies looking to expand the scope and efficiency ofthe process. Included amongst these developments are studiesaimed at developing Cu-free processes (in order to reduceCu-catalyzed Glaser-type alkyne homo-dimerization, and to reducethe environmental impact),3 transition metal-free processes,4 andexpanding the range of, and consequently selectivity between,leaving groups.2 Whilst simple aryl/alkenyl iodides, bromides,chlorides and triflates have provided a plethora of examples undera number of reaction conditions, selectivity for reaction with onehalide/pseudohalide over another has not proven straightforward.Use of a Ni-catalyst by Hu and co-workers in 2009 has shownpromising levels of selectivity by exploiting the innate reactivity ofalkyl chlorides, bromides and iodides; however, this work did notdeal with aryl substitution, and other than by redesigning thesubstrate, there is no way to reverse the selectivity.5 A number oflaboratories have looked at using C–H functionalisation chemistryto overcome this problem with some success, however, the use ofsimple terminal alkynes as the coupling partner remains rare,6with haloalkynes,7 or hypervalent iodine reagents8 being thereagents of choice in ‘‘inverse Sonogashira coupling reactions’’.The activation of carbon–sulfur bonds, an area of interest inthe Willis laboratory for a number of years, has seen significantexpansion beyond the simple Kumada coupling in recentdecades.9 Reactions such as the Liebeskind–Srogl couplingare now regularly employed in both academic and industriallaboratories.10 Many of these processes employ catalysts notknown for their reactivity with aryl halides, and as a result anumber of orthogonal processes have been developed, almostexclusively on highly activated heteroaromatic scaffolds.11Reports of desulfitative alkynylation are rare, and involveactivation of the sulfide component,12 metallated alkynes,13 orare the result of the coupling of alkynyl thioethers with organo-metallic reagents.14 Our laboratory has recently demonstratedthat, in combination with a suitable directing group, it is possible touse Rh–bisphosphine complexes to selectively activate the C–S bondof arylmethylsulfides, to effect carbothiolation reactions,15reductive desulfurisations,16 or Suzuki-type cross coupling reactions(Scheme 1).17 As full selectivity for C–S functionalisation over C–Xfunctionalisation was in each case observed, we envisaged thatScheme 1 Existing C–S activation methodologies and proposed chemo-selective Sonogashira-type coupling.Department of Chemistry, University of Oxford, Chemistry Research Laboratory,Mansfield Road, Oxford, OX1 3TA, UK. E-mail: michael.willis@chem.ox.ac.uk† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cc00092eReceived 4th January 2019,Accepted 25th January 2019DOI: 10.1039/c9cc00092ersc.li/chemcommChemCommCOMMUNICATIONOpen Access Article. Published on 14 February 2019. Downloaded on 2/20/2019 12:01:03 PM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineView JournalChem. Commun. This journal is©The Royal Society of Chemistry 2019similar methodology would enable us to develop an orthogonalSonogashira-type process simply by switching the boronic acidcoupling partner with a terminal alkyne.Whilst terminal alkynes had previously been used as thecoupling partner in the carbothiolation procedure, we anticipatedthat the use of a thiophilic Cu-co-catalyst would favor thealkynylation over carbothiolation, thus providing an example ofcatalyst-controlled divergence of reactivity. Initial investigationsinvolved the combination of 2-(methylthio)acetophenone (1a)and phenylacetylene (2a). By using the hemilabile bisphosphineligand DPEphos in combination with [Rh(nbd)2]BF4, copperiodide and potassium carbonate (Table 1, entry 1), a conversionof 25% was recorded to product 3a. By switching to the more rigidXantPhos ligand, the conversion dropped to 13% and the productof carbothiolation (4) was also observed (entry 2). Moving towardssmall bite-angle PCP-bisphosphines, such as dppm and dcpm(entries 3 and 4), did not show much improvement, however,with the PCCP ligands dppe and dcpe (entries 5 and 6, respec-tively), considerably higher conversions were achieved. Whilst theconversion was lower with dcpe than with dppe, the improvedselectivity made it an attractive choice for further optimization. Afterevaluating a number of bases, it was found that silver carbonatecould improve the conversion to 61% (entry 7). Experimenting withvarious copper sources (entries 8–11) resulted in conversions of upto 93%; however, the breakthrough came with the use of copperbromide (entry 12). Not only was full consumption of the startingmaterial now observed, but only product 3a was observed inthe 1H-NMR spectrum of the crude reaction mixture. Thishigh conversion and selectivity was reflected in the excellentisolated yield of 95%. Aware that the use of stoichiometricsilver carbonate could be costly on a larger scale, alternativeconditions employing potassium carbonate were also developed(entry 13).With efficient conditions for the formation of Sonogashira-product 3a in hand, we moved on to investigate the range ofterminal alkynes compatible with this chemistry (Scheme 2).Aromatic alkynes proved excellent substrates, with high yieldsobserved for both electron-rich (3b) and electron-poor (3c and d)aryl groups, as well as heteroaromatic alkynes (3e). As anticipated,the Rh-complex exhibited high selectivity for reaction with thecarbon–sulfur bond over that of the carbon–halide bond presentin 3c. Alkyl alkynes performed more poorly with the standardsubstrate (3f–i), however we were pleased to observe that withalternative directing groups, excellent yields were still possible(3g). Sterically bulky groups such as tert-butyl (3h) or theremovable TIPS group (3j) were well tolerated. By using conditionsA, it was possible to perform the reaction on a 30.0 mmol scale,using only 2.5 mol% of the active rhodium catalyst, deliveringdiaryl alkyne 3a in a 96% yield.As shown in Scheme 3, exploration of the scope of the aryl-methylsulfide component was similarly successful, with electron-rich (3k) and electron-poor (3l–o) examples each reacting in goodto excellent yields. The generation of halide containing productsallows for further functionalisation. It was additionally demonstratedthat more complex functionality could be tolerated elsewhere onthe scaffold (3p).As previously mentioned, a major strength of rhodium(I)catalysis lies in the extremely high selectivity for the activationof one bond, in this case the C–S bond, in the presence of othereasily activated bonds, which could not be carried througha reaction sequence if using palladium catalysis, for example.In order to demonstrate the orthogonality of these processes,Table 1 Optimization of Sonogashira conditionsEntry Ligand Cu source Additive Conversiona1 DPEphos CuI K2CO3 25%2 Xantphos CuI K2CO3 13% (5%)3 dppm CuI K2CO3 19% (5%)4 dcpm CuI K2CO3 30%5 dppe CuI K2CO3 48% (7%)6 dcpe CuI K2CO3 40%7 dcpe CuI Ag2CO3 61% (12%)8 dcpe CuI (2 eq.) Ag2O 84% (8%)9 dcpe CuI (2 eq.) Ag2CO3 93% (5%)10 dcpe CuTc Ag2CO3 —11 dcpe Cu(OAc) Ag2CO3 —12 dcpe CuBr (2 eq.) Ag2CO3 100%, 95%b13 dcpe CuBr (4 eq.) K2CO3 (2 eq.) 100%a Conversions determined by 1H NMR spectroscopic analysis of thecrude reaction mixture, value in parentheses indicates conversion tocarbothiolation product 4. b Isolated yield of 3a.Scheme 2 Scope of alkyne component in Sonogashira-type couplingreactions.Communication ChemCommOpen Access Article. Published on 14 February 2019. Downloaded on 2/20/2019 12:01:03 PM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineThis journal is©The Royal Society of Chemistry 2019 Chem. Commun.we first exposed compound 5, featuring both aryl bromideand methylsulfide functional groups, to our Rh(I)-catalyzed C–SSonogashira conditions, followed by traditional Pd(0)-catalyzedSonogashira conditions for the generation of dialkyne 7(Scheme 4). Each reaction proceeded in a very good yield, andthe same product (7), was obtained by switching the order ofthe two transition metal-catalyzed processes.Our laboratory has previously demonstrated that in situgenerated Rh–dcpe complexes are effective catalysts for alkeneand alkyne hydroacylation reactions,18 and we were thereforeintrigued by the possibility of conducting a tandem hydroacylation-Sonogashira sequence, resulting in the three-component couplingof an aldehyde with two distinct alkynes, forming two new C–Cbonds, using a single rhodium catalyst (Scheme 5). Such a processwould be a powerful method to rapidly build up molecularcomplexity from simple, commercially available building blocks.We began by reducing potential complications by using the samealkyne for both steps of the reaction, with fluoro-substitutedphenylacetylene affording the product (9a) in good yield over twoScheme 3 Scope of arylmethylsulfide component.Scheme 4 Reversible selectivity between Rh- and Pd-catalyzed Sonogashirareactions.Scheme 5 Tandem hydroacylation-Sonogashira sequence.Scheme 6 Tandem reactions for the synthesis of heterocycles andextended ring systems.ChemComm CommunicationOpen Access Article. Published on 14 February 2019. Downloaded on 2/20/2019 12:01:03 PM.  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.View Article OnlineChem. Commun. This journal is©The Royal Society of Chemistry 2019steps. We were pleased to discover that the use of differing alkynesfor each step was also easily achieved. A range of alkynes wasemployed, generating hydroacylation-Sonogashira products 9b–g.Compound 9g, in particular, contains synthetic handles for furtherfunctionalisation on each of the constituent components, whichwould be extremely difficult to prepare using Pd- or Ni-catalyzedmethods.Further reaction sequences, generating increasingly complexproducts were subsequently attempted, as depicted in Scheme 6.By employing suitably protected propargyl amines as substratesfor the first step in the hydroacylation-Sonogashira sequence,19 athree-step, two-pot synthesis of highly functionalised pyrrole 11was achieved in a good yield, requiring only a single chromato-graphic purification to obtain the pure heterocycle. An alternativesequence resulted in the combination of the hydroacylation-Sonagashira steps with a p-acid-catalysed [4+2]-cycloadditionreaction between an isochromenylium ion and a styrene derivate,ultimately yielding 1,2-dihydronaphthylene 13 after subsequentring opening of the bicyclic intermediate. Such processes havebeen effected by a number of p-acids, and the conditions usedherein were first reported by Yamamoto et al. in 2003.20In conclusion, we have developed a novel Sonogashira-typecoupling between arylmethylsulfides and terminal alkynes. Utilizingan electrophilic Rh–bisphosphine catalyst system, the reactionhas been shown to exhibit tolerance to a broad range offunctional groups, many of which would not be tolerated underalternative TM-catalysis. This selectivity has been demonstratedin the orthogonal activation of either a C–S bond or C–X bond byeither Rh or Pd respectively. In addition, the reactions reported hereshow how divergent reactivity for the same reaction componentscan be achieved by catalyst and reagent selection, with Sonogashiraand not carbothiolation products being obtained.Conflicts of interestThere are no conflicts to declare.Notes and references1 (a) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett.,1975, 16, 4467; (b) L. Cassar, J. Organomet. Chem., 1975, 93, 253;(c) H. A. Dieck and F. R. Heck, J. Organomet. Chem., 1975, 93, 259.2 R. Chinchilla and C. Nájera, Chem. Rev., 2007, 107, 874.3 (a) V. P. W. Böhm and W. A. Hermmann, Eur. J. Org. Chem., 2000,3679; (b) B. H. Lipshutz, D. W. Chung and B. Rich, Org. Lett., 2008,10, 3793; (c) L. Dong-Hwan, H. Qiu, M.-h. Cho, I.-M. Lee andM.-J. Jin, Synlett, 2008, 1657; (d) Y. Liang, Y.-X. Xie and J.-H. Li,J. Org. Chem., 2006, 71, 379; (e) V. K. Kanuru, S. M. Humphrey,J. M. W. Kyffin, D. A. Jefferson, J. W. Burton, M. Armbrüster andR. M. Lambert, Dalton Trans., 2009, 7602.4 (a) P. 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A rhodium-catalysed Sonogashira-type coupling exploiting C–S functionalisation: orthogonality with palladium-catalysed variants

A rhodium-catalysed Sonogashira-type coupling exploiting C–S functionalisation: orthogonality with palladium-catalysed variants

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