From Europe PMC via Jisc Publications RouterHistory: ppub 2020-03-01, epub 2020-03-31Publication status: PublishedFunder: Engineering and Physical Sciences Research Council; Grant(s): EP/L014017/2Over the last few decades C-H olefination has received significant interest, due to the importance and usefulness of aryl olefins both as synthetic targets and intermediates. While a wide range of ortho-olefination protocols have been developed, only a small number of meta-olefinations are currently available. Importantly, the most common approach to meta-olefination, using a large meta-directing template, is not suitable for substrates such as fluorobenzenes, which cannot be derivatised. We report that the meta-selective olefination of fluoroarenes can be achieved via the use of CO2 as a traceless directing group, which can be easily installed and removed in a one-pot process. Furthermore, this approach avoids the use of stoichiometric Ag(i)-salts, commonly used in C-H olefinations, and affords complete meta- over ortho/para-regioselectivity

Font, Marc

Korde, Rishi

Larrosa, Igor

Spencer, Andrew R A

English

ChesterRep

ChemicalScienceEDGE ARTICLEmeta-Selective oSchool of Chemistry, University of ManchesUK. E-mail: igor.larrosa@manchester.ac.uk† Electronic supplementary informa10.1039/d0sc01138jCite this: Chem. Sci., 2020, 11, 4204All publication charges for this articlehave been paid for by the Royal Societyof ChemistryReceived 25th February 2020Accepted 31st March 2020DOI: 10.1039/d0sc01138jrsc.li/chemical-science4204 | Chem. Sci., 2020, 11, 4204–4lefination of fluoroarenes withalkynes using CO2 as a traceless directing group†Andrew R. A. Spencer, Rishi Korde, Marc Font and Igor Larrosa *Over the last few decadesC–Holefination has received significant interest, due to the importance and usefulnessof aryl olefins both as synthetic targets and intermediates. While a wide range of ortho-olefination protocols havebeen developed, only a small number of meta-olefinations are currently available. Importantly, the mostcommon approach to meta-olefination, using a large meta-directing template, is not suitable for substratessuch as fluorobenzenes, which cannot be derivatised. We report that the meta-selective olefination offluoroarenes can be achieved via the use of CO2 as a traceless directing group, which can be easily installedand removed in a one-pot process. Furthermore, this approach avoids the use of stoichiometric Ag(I)-salts,commonly used in C–H olefinations, and affords complete meta- over ortho/para-regioselectivity.IntroductionOver the last decades, direct C–H bond activation has emergedas a powerful tool providing a wide variety of novel disconnec-tions simplifying access to, and accelerating the synthesis ofcomplex molecules.1 Aryl olens are synthetically importantmotifs, as useful intermediates in synthesis,2 and also due totheir widespread presence in bioactive molecules and phar-maceuticals.3 Consequently, large efforts have been devoted tothe development of C–H olenation methodologies.4 Whilea large number of strategies have been developed for the ole-nation of C–H bonds ortho to a directing group,5 comparativelyfew exist for those inmeta positions.6 To date, the only available‘direct’ strategy for meta-olenation, involves the use of the U-shaped directing groups pioneered by the group of Yu(Scheme 1a).7 This approach has been used to perform meta-olenations on derivatives of benzyl alcohols,8 N-methylanilines,9 phenyl acetic acids,10 benzyl sulfonyl esters,11 benzoicacids,12 aromatic carbonyls13 and aryl boronic acids,14 usingalkenes as coupling partners. The major drawback of thisapproach arises from the need to install the large U-shapeddirecting group, covalently bound, and its subsequentremoval aer the C–H olenation, as separate synthetic steps.In addition, stoichiometric toxic Ag(I)-salts are required asterminal oxidants in these oxidative couplings. A recent reporthas expanded the applicability of this strategy to the Rh(III)-catalysed meta-olenation of hydrocinnamic acid derivativesusing alkynes as coupling partners (Scheme 1b).15 However,despite it being a redox neutral process, it still requires overter, Oxford Road, Manchester, M13 9PL,tion (ESI) available. See DOI:208three equivalents of Ag(I)-salts as an additive. Furthermore, inaddition to the main meta-olenation product, 5–10% of thesometimes difficult to separate ortho and para olenationproducts are typically obtained. Additionally, the U-shapeddirecting group strategy is only applicable to aromatics con-taining a group that can be easily derivatised.Scheme 1 Comparison of the template approach and the tracelessdirecting group relay strategy for the meta olefination of arenes.This journal is © The Royal Society of Chemistry 2020Table 1 Optimisation of catalyst. Yields were determined by 19F NMRanalysis using 1-bromo-4-fluorobenzene as an internal standardEntry [Ru] 3aa (yield%)1a Ru(p-cymene)(CO2Mes)2 812b Ru(p-cymene)(CO2Mes)2 603 Ru(p-cymene)(CO2Mes)2 864 [Ru(tBuCN)6][BF4]2 05 [Ru(C6H6)(OPiv)2] 256 [Ru(C6Me6)(OAc)2] 93a Without LiOAc and AcOH. b Without AcOH.Edge Article Chemical ScienceFluoroarenes are recurring structural motifs in pharmaceu-ticals, agrochemicals, organic materials and other biologicallyrelevant compounds.16 Approximately 30% of pharmaceuticalsand 40% of agrochemicals currently contain at least one uo-rine atom, usually at the aromatic ring.16 Thus, the direct C–Hfunctionalisation of monouorobenzenes can providestraightforward access to valuable materials (Fig. 1).3b–d Whilemonouoroarenes generally present low reactivity towardsdirect C–H olenation, a number of examples have been re-ported that use the arene as cosolvent to achieve ortho, para-selective olenation.17 Some pioneering methods for directolenation using the uoroarene as the limiting reagent havebeen reported by Yu et al., but mixtures of ortho, meta and parasubstitution are obtained.18 However, meta-selective olenationhas never been achieved. Importantly, the U-shaped directinggroup strategy cannot be applied to this class of substrates. Wehave previously shown that CO2 can be used as a tracelessdirecting group for the meta-selective arylation of phenols, u-orobenzenes and anisoles (Scheme 1c).19 The process relies onthe easy carboxylation of these aromatic substrates, to installa temporary carboxylate directing group. The carboxylate canthen direct the arylation before it is cleaved, in a tandemprocess, thus allowing a one-pot meta-arylation to proceed.However, the CO2 traceless directing group approach has neverbeen demonstrated on any other type of functionalisation.Herein we report the rst example of a meta-olenation of u-orobenzenes (Scheme 1d). This ruthenium-catalysed processinvolves the in situ installation and removal of a carboxylate,from CO2, uses alkynes as coupling partners and avoids theneed for stoichiometric use of Ag(I)-salts.Results and discussionWe have previously developed an optimised protocol for thelithiation/carboxylation of uoroarenes suitable for combina-tion in a one-pot process with a Pd-catalysed tandem arylation/protodecarboxylation, leading to the meta-arylation of uo-roarenes.19c In 2016, three methods for the Ru-catalysed tandemortho-olenation/protodecarboxylation of benzoic acids byhydroarylation of alkynes were reported by Hartwig and Zhao,20Ackermann21 and Gooben.22 Miura and co-workers have alsoFig. 1 Commercially available pharmaceuticals containing a metaalkenyl fluoroarene.This journal is © The Royal Society of Chemistry 2020reported numerous methods for the ortho-olenation/protodecarboxylation of benzoic acids using acrylates andstyrenes as coupling partners.23 We envisaged these methodscould be ideally adapted to operate in combination with thedirected ortho-metalation/carboxylation approach to furnish thedesired meta-olenation of uorarenes.We started our investigation by probing the decarboxylativeolenation of the uorotoluic acid 1a with diphenyl acetylene(2a), using Ackermann's protocol (Table 1, entry 1).21 To eval-uate the effect of the installation of the carboxylic acid usingortho-lithiation during the desired one-pot process we tested theaddition of 2 equiv. of LiOAc (entry 2), revealing a signicantnegative effect in reactivity. Gratifyingly, addition of 3 equiv. ofAcOH efficiently reversed the effect of the presence of the Li-salt(entry 3), providing a method to ensure compatibility of theprotocol with the carboxylation step. In previous work on Ru-catalysed ortho-arylation of polyuorobenzenes we observedan inhibitory effect of coordinated p-cymene, leading to thedevelopment of the arene-free Ru-precatalyst [Ru(tBuCN)6][BF4]2.24 However, the use of this catalyst in the olenationreaction led to no product formation (entry 4), suggesting theh6-coordinated arene is essential for reactivity towards olena-tion. Accordingly, the weaker coordinating benzene-complexled to poor reactivity (entry 5), whereas the highly coordi-nating C6Me6-bearing Ru complex gave an improved yield, aneffect which has previously been observed by Gooben.25We then moved to optimize the full one-pot protocol, start-ing from ortho-uorotoluene (4a, Table 2). Carboxylation of theuoroarene was observed to occur in nearly quantitativeconversion using secBuLi at 78 C for 30 min, followed byquenching with CO2. Subsequent addition to the same ask ofAcOH (3 equiv.), alkyne 2a and 5 mol% Ru(C6Me6)(OAc)2 in DCEled to the formation of the meta-olenated product 3aa in anexcellent 85% yield (entry 1). The use of 4 equiv. or 5 equiv. ofAcOH led to reduced yields (entries 2 and 3). Examination ofother organic acids also led to lower yields (entries 4–6),Chem. Sci., 2020, 11, 4204–4208 | 4205Table 2 Optimisation of one-pot protocol. Yields were determined by19F NMR analysis using 1-bromo-4-fluorobenzene as an internalstandardEntry Acid (equiv.)4aa(yield%)1 AcOH (3) 852 AcOH (4) 753 AcOH (5) 724 PivOH (3) 15 iBuCOOH (3) 716 TFA (3) 5Chemical Science Edge Articlerevealing AcOH as the optimal acid to facilitate this one-potprocess.With the optimised conditions in hand, we investigated thegenerality of the process with regards to the uoroarene core(Scheme 2). Substitution patterns in ortho, meta or para posi-tions were all tolerated, albeit only the relatively small F-atomwas compatible in para (3ad). When larger groups wereinstalled in the para position such as Me and Cl, no reactivitycould be observed (3al and 3am). Furthermore, the reaction is inall cases completely selective towards mono-olenation andtowards the meta position, with no traces of neitherScheme 2 Scope in fluoroarene core. a10 mol% catalyst used.4206 | Chem. Sci., 2020, 11, 4204–4208bisolenation nor other regioisomers observed by NMR andGCMS analysis of the reactions, even for simple uorobenzene(3ab). Both electron withdrawing groups (3ac, 3ad, 3ag and 3ah)and donating groups (3aa, 3ae, 3af and 3aj) were compatiblewith the procedure. Chloroarenes (3ah) were also tolerated withno traces of de-halogenated products. Biaryl and naphthyl-based aromatic systems were also suitable substrates (3ai and3ak).Subsequently we investigated the scope with respect to thealkyne coupling partner (Scheme 3). Both electron donating(3ba and 3ca) and electron withdrawing groups (3da, 3ea and3fa) were reactive giving excellent yields. Heterocyclic moietieswere also tolerated (3ga). While bisalkyl acetylenes wereincompatible with the procedure (3la), unsymmetrical alkyl,aryl-acetylenes led to completely regioselective addition at thecarbon adjacent to the alkyl group (3ha and 3ia). Diesters andunsymmetrical ester, aryl-acetylenes were also tolerated offeringa handle for further functionalisation (3ja and 3ka) with ethylphenyl propiolate preferentially forming the a-aryl ester (3ja).No product was observed when terminal acetylenes were used(3ma).This new meta-olenation methodology can be easily scaledup with, for example, 3aa being formed in 70% yield (1.10 g)without any changes to the protocol.Scheme 3 Scope in acetylene. a10 mol% catalyst used.This journal is © The Royal Society of Chemistry 2020Scheme 4 Plausible mechanism for the Ru catalysedmeta olefinationof fluoroarenes.Edge Article Chemical ScienceA plausible mechanism for this transformation is shown inScheme 4, based on the mechanistic studies performed byHartwig and Zhao.20 ortho-Lithiation and carboxylation of uo-roarene 4 affords lithium benzoate 5. ortho-C–H activation oflithium benzoate 5 with ruthenium complex 6a affords cyclo-metallated complex 6b. Insertion of alkyne 2a into the Ru–C of6b forms complex 6c, which can in turn decarboxylate to fromthe 5-membered metallocycle in complex 6d. Protonation ofthis complex with 2 equiv. of AcOH liberates the nal product 3and reforms complex 6a, thus closing the catalytic cycle.ConclusionsIn conclusion, we have developed the rst example of a meth-odology for the meta-selective olenation of uoroarenes. Thenatural ortho, para-reactivity of this class of substrates has beenovercome by employing CO2 as a traceless directing group, thatcan be installed, used to control reactivity and then seamlesslyremoved in a one-pot process. Good to excellent yields can beobtained with a variety of functional groups and substitutionpatterns in both uoroarene and alkyne, and in all casescomplete meta-regioselectivity is observed.Conflicts of interestThere are no conicts to declare.AcknowledgementsWe gratefully acknowledge the Engineering and PhysicalSciences Research Council (EPSRC, EP/L014017/2) and theMarie Skłodowska Curie actions (IF-656841 to MF) for funding.This journal is © The Royal Society of Chemistry 2020Notes and references1 (a) R. H. Crabtree, Chem. Rev., 1985, 85, 245–269; (b) A. E. Shilovand G. B. Shul'pin, Chem. Rev., 1997, 97, 2879–2932; (c)J. A. Labinger and J. E. Bercaw, Nature, 2002, 417, 507–514; (d)R. G. Bergman, Nature, 2007, 446, 391–393; (e) D. Alberico,M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174–238; (f)X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem.,Int. Ed., 2009, 48, 5094–5115; (g) L. Ackermann, R. Vicente andA. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792–9826; (h)C.-J. Li, Acc. Chem. Res., 2009, 42, 335–344; (i) J. Wencel-Delord,T. Dröge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40,4740–4761; (j) C. S. Yeung and V. M. Dong, Chem. Rev., 2011,111, 1215–1292; (k) M. Tobisu and N. Chatani, Science, 2014,343, 850–851; (l) M. Simonetti, D. M. Cannas and I. Larrosa,Adv. Organomet. Chem., 2017, 67, 299–399.2 Selected examples of aryl olens as intermediates for thesynthesis of bioactive molecules (a) T. Nishimata, Y. Satoand M. Mori, J. Org. Chem., 2004, 69, 1837–1843; (b)L. V. White, B. D. Schwartz, M. G. Banwell and A. C. Willis,J. Org. Chem., 2011, 76, 6250–6257; (c) C. Singh,M. Hassam, V. P. Verma, A. S. Singh, N. K. Naikade,S. K. Puri, P. R. Maulik and R. Kant, J. Med. Chem., 2012,55, 10662–10673.3 Examples of aryl olens in bioactive molecules (a) J. Joseph-Charles and M. Bertucat, Anal. Chim. Acta, 1993, 284, 45–52;(b) D. B. Mendel, A. D. Laird, X. Xin, S. G. Louie,J. G. Christensen, G. Li, R. E. Schreck, T. J. Abrams,T. J. Ngai, L. B. Lee, L. J. Murray, J. Carver, E. Chan,K. G. Moss, J. Ö. Haznedar, J. Sukbuntherng, R. A. Blake,L. Sun, C. Tang, T. Miller, S. Shirazian, G. McMahon andJ. M. Cherrington, Clin. Cancer Res., 2003, 9, 327–337; (c)S. Hirankarn, J. S. Barrett, N. Alamuddin, G. A. FitzGeraldand C. Skarke, Clin. Pharmacol. Drug Dev., 2013, 2, 379–386; (d) J. Qian, Y. Wang, J. Cao and J. Li, J. Pharm. Biomed.Anal., 2013, 80, 173–179.4 Selected reviews on C–H olenation of arenes (a) C. Nevadoand A. M. Echavarren, Synthesis, 2005, 2, 167–182; (b)V. P. Boyarskiy, D. S. Ryabukhin, N. A. Bokach andA. V. Vasilyev, Chem. Rev., 2016, 10, 5894–5986; (c) W. Ma,P. Gandeepan, J. Li and L. Ackermann, Org. Chem. Front.,2017, 4, 1435–1467.5 Selected examples of ortho C–H olenation (a) G. Cai, Y. Fu,Y. Li, X. Wan and Z. Shi, J. Am. Chem. Soc., 2007, 129, 7666–7673; (b) L. Wang, S. Liu, Z. Li and Y. Yu, Org. Lett., 2011, 13,6137–6139; (c) B. Liu, H.-Z. Jiang and B.-F. Shi, J. Org. Chem.,2014, 79, 1521–1526; (d) A. Deb, S. Bag, R. Kancherla andD. Maiti, J. Am. Chem. Soc., 2014, 136, 13602–13605; (e)G. Li, L. Wan, G. Zhang, D. Leow, J. Sprangler and J.-Q. Yu,J. Am. Chem. Soc., 2015, 137, 4391–4397.6 Selected reviews on meta selective C–H functionalisation (a)J. Yang, Org. Biomol. Chem., 2015, 13, 1930–1941; (b) J. Lie,S. De Sarkar and L. Ackermann, Top. Organomet. Chem.,2015, 55, 217–257; (c) A. Dey, S. Agasti and D. Maiti, Org.Biomol. Chem., 2016, 14, 5440–5453; (d) J. A. Leitch andC. G. Frost, Chem. Soc. Rev., 2017, 46, 7145–7153.Chem. Sci., 2020, 11, 4204–4208 | 4207Chemical Science Edge Article7 D. Leow, G. Li, T.-S. Mei and J.-Q. Yu, Nature, 2012, 486, 518–522.8 (a) S. Lee, H. Lee and K. L. Tan, J. Am. Chem. Soc., 2013, 135,18778–18781; (b) S. Fang, X. Wang, F. Yin, P. Cai, H. Yangand L. Kong, Org. Lett., 2019, 21, 1841–1844.9 R.-Y. Tang, G. Li and J.-Q. Yu, Nature, 2014, 507, 215–220.10 (a) M. Bera, A. Modak, T. Patra, A. Maji and D. Maiti, Org.Lett., 2014, 16, 5760–5763; (b) Y. Deng and J.-Q. Yu, Angew.Chem., Int. Ed., 2015, 54, 888–891.11 (a) M. Bera, A. Maji, S. K. Sahoo and D. Maiti, Angew. Chem.,Int. Ed., 2015, 54, 8515–8519; (b) M. Brochetta, T. Borsari,S. Bag, S. Jana, S. Maiti, A. Porta, D. B. Werz, G. Zanoniand D. Maiti, Chem.–Eur. J., 2019, 25, 10323–10327.12 S. Li, L. Cai, H. Ji, L. Yang and G. Li, Nat. Commun., 2016, 7,10443.13 S. Xie, S. Li, W. Ma, X. Xu and Z. Jin, Chem. Commun., 2019,55, 12408–12411.14 A. F. Williams, A. J. P. White, A. C. Spivey and C. J. Cordier,Chem. Sci., 2020, 11, 3301–3306.15 H.-J. Xu, Y.-S. Kang, H. Shi, P. Zhang, Y.-K. Chen, B. Zhang,Z.-Q. Liu, J. Zhao, W.-Y. Sun, J.-Q. Yu and Y. Lu, J. Am. Chem.Soc., 2019, 141, 76–79.16 (a) P. Kirsch and M. Bremer, Angew. Chem., Int. Ed., 2000, 39,4216–4235; (b) W. R. Dolbier, J. Fluorine Chem., 2005, 126,157–163; (c) C. Isanbor and D. O'Hagan, J. Fluorine Chem.,2006, 127, 303–319; (d) F. Babudri, G. M. Farinola, F. Nasoand R. Ragni, Chem. Commun., 2007, 1003–1022; (e)M. Hird, Chem. Soc. Rev., 2007, 36, 2070–2095; (f)D. O'Hagan, Chem. Soc. Rev., 2008, 37, 308–319; (g)P. Jeschke, Pest Manage. Sci., 2010, 66, 10–27; (h) R. Berger,G. Resnati, P. Metrangolo, E. Weber and J. Hulliger, Chem.Soc. Rev., 2011, 40, 3496–3508; (i) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky,S. Fustero, V. A. Soloshonok and H. Liu, Chem. Rev., 2014,114, 2432–2506; (j) E. A. Ilardi, E. Vitaku andJ. T. Njardarson, J. Med. Chem., 2014, 57, 2832–2842; (k)4208 | Chem. Sci., 2020, 11, 4204–4208T. Fujiwara and D. O'Hagan, J. Fluorine Chem., 2014, 167,16–29; (l) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu,J. L. Aceña, V. A. Soloshonok, K. Izawa and H. Liu, Chem.Rev., 2016, 116, 422–518.17 (a) K. S. Kanyiva, N. Kashihara, Y. Nakao, T. Hiyama,M. Ohashi and S. Ogoshi, Dalton Trans., 2010, 39, 10483–10494; (b) C.-H. Ying, S.-B. Yan and W.-L. Duan, Org. Lett.,2014, 16, 500–503; (c) L. G. Y. Chung, N. A. B. Juwaini andJ. Seayad, ChemCatChem, 2015, 7, 1270–1274.18 (a) H. U. Vora, A. P. Silvestri, C. J. Engelin and J.-Q. Yu,Angew. Chem., Int. Ed., 2014, 53, 2683–2686; (b) P. Wang,P. Verma, G. Xia, J. Shi, J. X. Qiao, S. Tao, P. T. W. Cheng,M. A. Poss, M. E. Farmer, K.-S. Yeung and J.-Q. Yu, Nature,2017, 551, 489–493.19 (a) J. Luo, S. Preciado and I. Larrosa, J. Am. Chem. Soc., 2014,136, 4109–4112; (b) J. Luo, S. Preciado, S. O. Araromi andI. Larrosa, Chem.–Asian J., 2016, 11, 347–350; (c) M. Font,A. R. A. Spencer and I. Larrosa, Chem. Sci., 2018, 9, 7133–7137.20 J. Zhang, R. Shrestha, J. F. Hartwig and P. Zhao, Nat. Chem.,2016, 8, 1144–1151.21 N. Y. P. Kumar, A. Bechtoldt, K. Raghuvanshi andL. Ackermann, Angew. Chem., Int. Ed., 2016, 55, 6929–6932.22 L. Huang, A. Biafora, G. Zhang, V. Bragoni and L. J. Gooßen,Angew. Chem., Int. Ed., 2016, 55, 6933–6937.23 (a) A. Maehara, H. Tsurugi, T. Satoh and M. Miura, Org. Lett.,2008, 10, 1159–1162; (b) S. Mochida, K. Hirano, T. Satoh andM. Miura, Org. Lett., 2010, 12, 5776–5779; (c) S. Mochida,K. Hirano, T. Satoh and M. Miura, J. Org. Chem., 2011, 76,3024–3033.24 M. Simonetti, G. J. P. Perry, X. C. Cambeiro, F. Juliá-Hernández, J. N. Arokianathar and I. Larrosa, J. Am. Chem.Soc., 2016, 138, 3596–3606.25 A. Biafora, B. A. Khan, J. Bahri, J. M. Hewer and L. J. Gooben,Org. Lett., 2017, 19, 1232–1235.This journal is © The Royal Society of Chemistry 2020

<i>meta</i>-Selective olefination of fluoroarenes with alkynes using CO<sub>2</sub> as a traceless directing group.

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<i>meta</i>-Selective olefination of fluoroarenes with alkynes using CO<sub>2</sub> as a traceless directing group.

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