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HFO-1234Yf As a CF3-Building Block : Synthesis and Chemistry of CF3-Ynones.', European Journal of Organic Chemistry., 2020 (39)

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HFO-1234Yf As a CF3-Building Block : Synthesis and Chemistry of CF3-Ynones.', European Journal of Organic Chemistry., 2020 (39) Durham Research Online Deposited in DRO: 23 October 2020 Version of attached le: Published Version Peer-review status of attached le: Peer-reviewed Citation for published item: Murray, Ben J. and Marsh, Thomas G. F. and Yut, Dmitri S. and Fox, Mark A. and Harsanyi, Antal and Boulton, Lee T. and Sandford, Graham (2020) 'HFO-1234yf as a CF3-building block : synthesis and chemistry of CF3-ynones.', European journal of organic chemistry., 2020 (39). pp. 6236-6244. Further information on publisher's website: https://doi.org/10.1002/ejoc.202001071 Publisher's copyright statement: c 2020 The Authors published by WileyVCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Additional information: Use policy The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full DRO policy for further details. Durham University Library, Stockton Road, Durham DH1 3LY, United Kingdom Tel : +44 (0)191 334 3042 | Fax : +44 (0)191 334 2971 https://dro.dur.ac.uk EurJOC Full Paper European Journal of Organic Chemistry doi.org/10.1002/ejoc.202001071 Fluorine Chemistry HFO-1234yf as a CF3-Building Block: Synthesis and Chemistry of CF3-Ynones Ben J. Murray,[a] Thomas G. F. Marsh,[a] Dmitri S. Yufit,[a] Mark A. Fox,[a] Antal Harsanyi,[b] Lee T. Boulton,[b] and Graham Sandford*[a] th Abstract: Reaction of low cost, readily available 4 generation philes to CF3-ynones are rapid and selective, affording a range refrigerant gas 2,3,3,3-tetrafluoropropene (HFO-1234yf) with of CF3-enone ethers and enaminones in excellent yields with lithium diisopropylamide (LDA) leads to formation of lithium high stereoselectivity for the Z-isomer. By analogous reactions 3,3,3-trifluoropropynide, addition of which to a range of alde- with difunctional nucleophiles, a wide range of CF3-substituted hydes formed CF3-alkynyl alcohol derivatives on multigram pharmaceutically relevant heterocyclic structures can be ac- scale, which were oxidised using Dess–Martin periodinane cessed, exemplified in the simple synthesis of the anti-arthritis (DMP) to give substituted CF3-ynones with minimal purification drug celecoxib from HFO-1234yf in just three steps. required. Michael-type additions of alcohol and amine nucleo- Introduction The introduction of fluorine atoms into therapeutic compounds is an important synthetic challenge because fluorination can impart well established beneficial effects to lipophilicity, meta- bolic stability, conformational preference and bioavailability.[1] In particular, the trifluoromethyl group is present in several re- nowned blockbuster drugs (Scheme 1a). However, incorpora- tion of the CF3 group into organic systems relies on either inex- pensive early stage processes (e.g. HF or SF4) for the synthesis of a relatively limited range of suitable trifluoromethyl building blocks, particularly aromatic compounds bearing a CF3 group and trifluoroacetic acid derivatives,[2] or milder, late-stage tri- fluoromethylating reagents (e.g. Me3Si-CF3,CF3SO2Na, CF3-di- benzothiophenium salts or CF3-hypervalent iodine species), the cost of which can be prohibitive on the manufacturing scale.[3] Scheme 1. (a) Well-known heterocyclic drug molecules bearing a CF3-group; New routes to CF3-substituted systems from low cost building (b) previously reported syntheses of CF3-ynones; (c) approach in this work. blocks under mild conditions are, therefore, highly desirable, particularly for the preparation of multi-functional derivatives bearing trifluoromethyl groups. given that ynones are well-known to be useful starting materi- als in a wide range of synthetically valuable reactions,[4] such In this context, it is surprising that trifluoromethyl-substi- as via tandem conjugate addition of dinucleophiles, through tuted ynones have received so little attention in the literature, various organocatalytic and transition-metal catalysed proc- esses as well as cycloaddition and hydrohalogenation reactions. [a] B. J. Murray, T. G. F. Marsh, Dr. D. S. Yufit, Dr. M. A. Fox, Prof. G. Sandford Department of Chemistry, Durham University, Whilst ynones with the CF3 group adjacent to the carbonyl [5] South Road, Durham, DH1 3LE, U.K. (CF3COC≡CR) are well known, as they can be derived from E-mail: [email protected] trifluoroacetic acid, ynones with a terminal alkynyl CF3 group https://www.dur.ac.uk/chemistry/staff/profile/?id=199 (RCOC≡CCF ) are unexpectedly rare; indeed, there have only [b] Dr. A. Harsanyi, Dr. L. T. Boulton 3 Medicines Research Centre, GlaxoSmithKline R&D Ltd, been six reports in the literature of this class of structure [6] Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K. (Scheme 1b). CF3-ynoates (CF3C≡CCO2R) are commercially Supporting information and ORCID(s) from the author(s) for this article are available, albeit expensive, and so their use is more widely re- available on the WWW under https://doi.org/10.1002/ejoc.202001071. ported in the literature but their synthesis typically requires © 2020 The Authors published by Wiley-VCH GmbH. · This is an open access thermolysis of the corresponding phosphoranes.[7] This proce- article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the dure requires high temperatures and also evolves acetylene gas, original work is properly cited. a significant safety hazard when applied on a large scale. Eur. J. Org. Chem. 2020, 6236–6244 6236 © 2020 The Authors published by Wiley-VCH GmbH EurJOC Full Paper European Journal of Organic Chemistry doi.org/10.1002/ejoc.202001071 In this work, we describe a new and efficient route to nient –10 °C, THF gave much lower conversion. This corro- CF3-ynones from 2,3,3,3-tetrafluoropropene (HFO-1234yf, 1; borates literature reports that 2 is more stable in diethyl ether Scheme 1c), which is an inexpensive 4th generation refrigerant than THF.[6e] However, diethyl ether is an undesirable solvent gas with low global warming potential.[8] Since HFO-1234yf is for process scales due to its volatility and tendency to form increasingly being manufactured on a very large scale for le- peroxides. Methyl tert-butyl ether (MTBE), a safer and more en- gally mandated use in automotive refrigeration systems in the vironmentally benign alternative to diethyl ether,[14] was found EU, the chemistry of HFO-1234yf has begun to be developed to give excellent conversion. Hence, using LDA in MTBE, tri- in the last few years.[9] However, HFO-1234yf has not yet seen fluoromethyl alcohol 3a was obtained in excellent yield and widespread use for the synthesis of more complex organic com- purity without the need for column chromatography or distilla- pounds and, in this paper, we show that CF3-ynones derived tion, requiring only a simple aqueous workup (Scheme 3). from 1 can be used to access a diverse variety of both aliphatic and aromatic CF3-containing compounds, through both intra- Table 1. Screening of conditions for addition of 2 to benzaldehyde to form and intermolecular reactions with nucleophiles. alcohol 3a; conversion determined by 19F NMR spectroscopy. Solvent Base Temperature /°C Conversion /% Et2O nBuLi –78 1 Results and Discussion Et2O LDA –78 82 Et2O LDA –10 97 We first observed that CF3-alkynes could be generated from 1 Et2O LTMP –10 14 [9a] whilst investigating nucleophilic substitution reactions of 1. Et2O LHMDS –10 0 THF LDA –78 82 Whilst oxygen- and sulfur-centered nucleophiles gave CF3-enol ethers and vinyl sulfides respectively, nitrogen- and carbon-cen- THF LDA –10 13 CPME LDA –10 91 tred nucleophiles proved to be unreactive with 1 under almost MTBE LDA –10 98 all conditions. An exception was alkyl, aryl or alkynyllithium rea- nBu2O LDA –10 70 gents and lithium or sodium amides, which caused elimination of lithium fluoride rather than the initially targeted nucleophilic addition-elimination reaction (Scheme 2). Formation of 3,3,3- 19 1 trifluoropropyne (CF3C≡CH) was observed by F and H NMR spectroscopy following quenching of the reaction mixture with [10] H2O(δH = 2.45 ppm, δF = –50.35 ppm; Figure S5 and S6). When the reaction mixture was instead quenched with D2O, Scheme 3. Optimised synthesis of trifluoromethyl alcohol 3a. the proton of 3,3,3-trifluoropropyne was no longer visible spec- troscopically. This confirmed that, not only was elimination oc- To gain further insight into the formation of 2 and 3a, the curring, but also that the resulting alkyne was deprotonated by reaction was monitored using in situ IR spectroscopy (Fig- the excess organolithium reagent to form lithium 3,3,3-trifluoro- ure 1).[15] This revealed that both the elimination to form 2 and propynide (CF3C≡CLi, 2) in situ. This method provides, therefore, its subsequent addition to benzaldehyde are near instantane- a simple procedure for generating versatile synthon 2 under ous, i.e. complete within 15 seconds. There also appeared to be relatively mild conditions from a more readily available feed- no significant side product formation and, indeed, isolation of stock than those used previously.[11] 3a proved facile. The same synthetic method was applied using a range of other aldehyde substrates to give trifluoromethyl alcohols 3b–3i on multigram scale with minimal purification required in each case, affording 68–95 % isolated yields (Table 2). A model reaction of 2 with benzoyl chloride was investigated Scheme 2.
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