Document mbawY2VjDEmKOZyDyOrQmvL5O

Chemistry--A European Journal Communication doi.org/1O.1OO2/chem.2O21O1621 1) Check for updates Europe European Chemical Societies Publishing 44 Radical C--H Trifluoromethoxylation of (Hetero)arenes with Bis(trifluoromethyl)peroxide Stefan Dix,[al Paul Golz,[a] Jonas R. Schrnid,[a] Sebastian Riedel,*[a] and Matthew N. Hopkinson*[a] Abstract: Trifluoromethoxylated (hetero)arenes are of great interest for several disciplines, especially in agro- and medicinal chemistry. Radical C--H trifluoromethoxylation of (hetero)arenes represents an attractive approach to prepare such compounds, but the high cost and low atom economy of existing 'OCF3 radical sources make them unsuitable for the large-scale synthesis of trifluoromethoxylated building blocks. Herein, we introduce bis(trifluoromethyl)peroxide (BTMP, CF3OOCF3) as a practical and efficient trifluoromethoxylating reagent that is easily accessible from inexpensive bulk chemicals. Using either visible light photoredox or TEMPO catalysis, trifluoromethoxylated arenes could be prepared in good yields under mild conditions directly from unactivated aromatics. Moreover, TEMPO catalysis allowed for the one-step synthesis of valuable pyridine derivatives, which have been previously prepared via multi-step approaches. Fluorinated agrochemicals and pharmaceuticals are of great importance due to the beneficial effects fluorine and fluorinated groups can have on a molecule's potency, metabolic stability, selectivity and toxicity.i11 In the last three decades, compounds containing one or more fluorine atoms made up 22% of all globally registered small-molecule drugs while, in the time period 1998-2020, 53% of all new agrochemicals were organofluorine compounds.Pu Trifluoromethoxylated arenes and heteroarenes are attracting increasing attention as up-and-coming fluorine-containing moieties. With a Hansch parameter (II= 1.04) in between that of SCF3 (1.44) and CF3 (0.88) and a notably lower electron-withdrawing influence than many other commonly employed fluorinated groups (op = 0.54 (CF3), 0.50 (SCF3), [a] S. Dix, P. Golz, J. R. Schmid, Prof. Dr. S. Riedel, Prof. M. N. Hopkinson Institute of Chemistry and Biochemistry Freie Universitat Berlin Fabeckstrasse 34-36, 14195 Berlin (Germany) E-mail: =@fu-berlin.de fu-berlin.de o Supporting information for this article is available on the WWW under https://doi.org/10.7002/chem.202707627 2021 The Authors. Published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 0.35 (OCF3)),[21 the OCF3 moiety allows for a fine-tuning of a molecule's biological activity and bioavailability. Furthermore, fluorine-specific stereoelectronic effects result in unconventional conformational preferences not encountered with other substituentsP1 To date, several drugs (e.g. Pretomanid, Delamanid, Sonidegib, Riluzol, Celikalim) and agrochemicals (e.g. lndoxacarb, Thifluzamide, Flurprimidol) featuring an Ar-OCF3 moiety, have been developed.[4] Despite this great potential, the study of OCF3-substituted (hetero)arenes has been hindered by the lack of practical methods to synthesize them.[41 Direct trifluoromethoxylation reactions, wherein the OCF3 moiety is installed as an intact functional group onto an arene or heteroarene are especially scarce. With no electrophilic sources of the OCF3 group available and cross-coupling methodologies hampered by the inherent instability of the - OCF3 anion towards (3-fluoride elimination, radical trifluoromethoxylation arguably represents the most attractive approach. In 2018, Ngai and co-workers reported a breakthrough in this area by introducing a bench stable reagent A (Scheme 1a) that provides the 'OCF3 radical upon photochemical activationP1 Subsequent reports by the groups of Ngai, Togni and Tang disclosed additional 'OCF3 a) Reported Reagents for the C-H Trifluoromethoxylation of (hetero)arenes CN NTf2 bench stable solids or liquids A (Ngai, 2018) NO2 N OTf N N CF3 OCF3 C (Ngai, 2018) OCF3 B (Togni, 2018) OO `S''OCF3 D (Tang, 2020) OCF3 radical formed upon SET or homolytic N-O bond cleavage expensive (all prepared from Togni I or Togni II reagents) b) This Work: Direct C-H Trifluoromethoxylation with BTMP [Ru(bpy)3](PF6)2 (1.5 mol%) blue LEDs OCF3 + CF3O-OCF3 X 5 eq (BTMP, 1 eq) or TEMPO (5-25 mol%), Na2CO3 or K2CO3 (1 eq) R X = C, N BTMP accessible in bulk from inexpensive chemicals Successful with pyridines Suitability for scale-up investigated Scheme 1. Radical C--H trifluoromethoxylation of (hetero)arenes. a) Previously reported reagents. b) This work: BTMP as a practical *OCF3 source. Chem. Eur. J. 2021, 27, 11554-11558 Wiley Online Library 11554 2021 The Authors. Published by Wiley-VCH GmbH Chemistry--A European Journal Communication doi.org/10.1002/chem.202101621 sources (B-D), which could be employed in radical CH trifluoromethoxylation reactions with unactivated arenes.[6] While these reagents are bench stable and convenient on a laboratory scale, each is prepared from either the Togni I or Togni II electrophilic trifluoromethylating reagents. The high cost of these precursors makes large-scale applications unpractical while stoichiometric amounts of organic by-products are produced, which must be separated from the reaction mixture. With the aim of developing a practical method suitable for larger scale production of trifluoromethoxylated arene and heteroarene building blocks, our attention was drawn to bis (trifluoromethyl)peroxide (BTMP, 1) as a potential source of *OCF3. This compound can be prepared on a large scale from the inexpensive bulk chemicals CO and F2, and is remarkably stable towards both thermal and photochemical decomposition.[7] A small number of studies demonstrate, however, that BTMP can transfer an OCF3 group onto organic substrates, although the forcing conditions (high temperature,[8] UVA light[9]) employed to activate the peroxide drastically limited the substrate scope and resulted in only low yields and selectivities. Here we report the successful application of BTMP as a practical trifluoromethoxylating reagent under mild conditions employing either visible light photoredox or TEMPO catalysis (Scheme 1b). Using both activation modes, trifluoromethoxylated arenes could be prepared in a single step from simple aromatic feedstocks. The potential of these methods for the production of valuable OCF3-containing building blocks is further demonstrated by the one-step preparation of (trifluoromethoxy)pyridines, which till now have been prepared via multi-step syntheses. In an initial experiment, BTMP (1, 1 eq.) was condensed into an acetonitrile solution containing the photocatalyst [Ru(bpy)3][PF6]2 (bpy = 2,2'-bipyridine, 1 mol%) and benzene (2 a, 10 eq.).[10] After 16 h irradiation with visible light from blue LEDs, we were delighted to observe efficient formation of (trifluoromethoxy)benzene 3 a in 48 % 19F NMR yield (internal standard = PhCF3). Working on the hypothesis that single electron transfer from the excited photocatalyst to BTMP followed by mesolysis results in *OCF3 formation, alternative single electron reductants were tested.[11] In addition to lightmediated activation of BTMP by various photocatalysts, the simple metal salt CuCl (1 eq.) also led to the formation 3 a in 50 % NMR yield without light irradiation. Photocatalysis with [Ru(bpy)3][PF6]2, however, remained the most efficient approach and optimization of the other reaction parameters led to a set of standard conditions that provided 3 a in 74 % NMR yield (1.5 mol% [Ru(bpy)3][PF6]2, 5 eq. 2 a, 0.1 eq. KF, 0.2 M MeCN, blue LEDs, rt, 16 h). The scope of the photocatalytic CH trifluoromethoxylation with a selection of aromatic feedstocks is shown in Scheme 2. A range of diverse substituents on the arene was tolerated, with electron-withdrawing groups generally leading to the highest yields. In most cases, BTMP provided similar yields of products 3 to those previously reported using reagents A-D. Deviations were observed, however, for benzonitrile 2 f and methyl benzoate 2 i with the corresponding trifluoromethoxylated arenes being delivered in significantly higher yields (3 f = 69 %, Scheme 2. Scope of the photocatalytic CH trifluoromethoxylation of arenes using BTMP. 19F NMR yields using PhCF3 as an internal standard, ratio ortho-/ meta-/para- determined by 19F NMR shown in brackets. aWith 0.1 eq. KF. 3 i = 73 %), while iodobenzene 2 e was much less efficiently converted (4 %). The successful synthesis of the halogenated arenes 3 c and 3 d as well as the boronic ester species 3 l is particularly noteworthy as these products can serve as OCF3containing building blocks for cross-coupling methodologies. The regioselectivity of the photocatalytic trifluoromethoxylation with BTMP also mirrored that obtained using the previously reported reagents A-D and reflects the inherent electronic properties of the aromatic substrates. In each case, only trace amounts of bis(trifluoromethoxy)arene side-products were observed in the crude reaction mixtures, while waste species derived from the OCF3 by-product could be readily removed upon aqueous work-up. Having developed a set of efficient photocatalytic conditions, we next sought to investigate alternative approaches for activating BTMP, which do not require light irradiation. While initial results had identified metal salts such as CuCl as suitable stoichiometric activators, we were drawn to the recent report from Ngai and co-workers using catalytic amounts of (2,2,6,6tetramethylpiperidin-1-yl)oxyl (TEMPO) as a single electron shuttle with reagent C.[6c] TEMPO is significantly less expensive than [Ru(bpy)3][PF6]2 while the avoidance of light irradiation brings practical advantages for potential large scale applications.[12] Benzene (2 a, 5 eq.) and BTMP (1 eq.) were thus reacted with TEMPO (25 mol%) and inexpensive K2CO3 (1 eq.) as a basic additive in MeCN (0.5 M) at rt overnight. Analysis of the reaction mixture by 19F NMR revealed the efficient formation of Chem. Eur. J. 2021, 27, 11554 - 11558 www.chemeurj.org 11555 2021 The Authors. Published by Wiley-VCH GmbH Chemistry--A European Journal Communication doi.org/10.1002/chem.202101621 (trifluoromethoxy)benzene 3 a in 70 % yield. Furthermore, the low polarity of TEMPO means that the benzene substrate can be used as the only solvent, with 3 a being delivered in 61 % 19F NMR yield under neat conditions. The efficiency of the TEMPO-catalyzed trifluoromethoxylation method with a selection of aromatics is shown in Scheme 3. As for the photocatalytic reaction, a range of electron-poor and electron-neutral examples could be successfully employed in generally moderate to good yields up to 81 %. While the cyano- and methyl ester-substituted derivatives 3 f and 3 i could also be prepared in good yields under neat conditions (3 f = 81 %, 3 i = 45 %), other examples reacted more efficiently using MeCN as solvent. In most cases, the yields were similar to those obtained under photocatalytic conditions, although nitrobenzene (2 m) was less efficiently converted using TEMPO (27 % vs. 54 %). Interestingly, however, significant differences were observed in the regioselectivities of the trifluoromethoxylation reactions under the two sets of conditions. The halogen-substituted arenes 2 b, 2 c and 2 d, for example, exhibited a notably increased preference for the ortho and, especially, para products under TEMPO catalysis, with this preference increasing in the order 3 d < 3c < 3b (i. e. Br < Cl < F). In fact, while the same broad regioselectivity trends were observed under both sets of conditions, TEMPO catalysis led to a higher selectivity for the para-(OCF3)-substituted products with each aromatic substrate tested. The observation that different activation modes lead to different product distributions is both potentially synthetically useful and mechanistically interesting as it implies that the regioselectivity is not simply a reflection of the substrate properties. At this stage of the study, we sought to explore BTMP as a practical reagent for the direct synthesis of hitherto underexplored OCF3-containing building blocks. Given the importance of nitrogen heterocycles in pharmaceuticals, (trifluoromethoxy)pyridines are highly desirable motifs for incorporation into new drug targets. Currently, however, these species are generally accessed via indirect methods. In comparison to benzene derivatives, such approaches entail additional synthetic steps as the (hydroxy)pyridine starting materials required for de novo construction of the OCF3 moiety are not widely available. Furthermore, the key halex step can only be achieved on -chloropyridine derivatives using the unattractive fluorinating agent SbF3.[13] In 2016, the groups of Zou, Wu and Wu reported a trifluoromethylation approach towards trifluoromethoxylated pyridines and pyrimidines. However, the use of the expensive Togni II reagent and the restriction to 2OCF3-substituted derivatives limits its applicability for the synthesis of diverse building blocks.[14,15] To assess the feasibility of direct CH trifluoromethoxylation of pyridine building blocks using BTMP, picolinonitrile 4 a was selected as a representative substrate featuring a functional group amenable to subsequent conversion into other useful moieties (e. g. through hydrolysis to a carboxylic acid). Reacting 4 a with BTMP under the optimized conditions with TEMPO provided the (trifluoromethoxy)pyridine 5 a in a 19F NMR yield of 35 % as a mixture of three regioisomers favoring the 5(trifluoromethoxy)picolinonitrile (23 % of 5 ab, Scheme 4). While the yield is only moderate, the direct synthesis of this species in a single step from 4 a represents a significant improvement on previously reported routes, which involved at least 6 steps from 2-aminopyridine.[16] A selection of further substrates featuring halogen, cyano and amino substituents were then reacted under both sets of optimized conditions and the product distribution was analyzed by 19F NMR and GC-MS (Scheme 5). In all cases, the desired (trifluoromethoxy)pyridines 5 were obtained in mostly moderate yields with TEMPO catalysis generally proving more efficient. Only with the 2-chloro-5-amino-substituted pyridine 4 f was a higher efficiency observed under photocatalytic conditions with 5 f being produced in 39 % 19F NMR yield (cf. 30 % using TEMPO). To the best of our knowledge, the successful conversion of substrates 4 e and 4 f represents the first time amino substituents have been tolerated in radical trifluoromethoxylation reactions. The more electron deficient Scheme 3. Scope of the TEMPO-catalyzed CH trifluoromethoxylation of arenes using BTMP. 19F NMR yields using PhCF3 as an internal standard, ratio ortho-/meta-/para- determined by 19F NMR shown in brackets. aTEMPO (5 mol%), no MeCN. bArene (10 eq.). Scheme 4. Synthesis of 5-(trifluoromethoxy)picolinonitrile 5 ab. a) Current approach: multi-step indirect synthesis. b) TEMPO-catalyzed trifluoromethoxylation with BTMP. 19F NMR yields (internal standard = PhCF3), isolated yields in parentheses. Chem. Eur. J. 2021, 27, 11554 - 11558 www.chemeurj.org 11556 2021 The Authors. Published by Wiley-VCH GmbH Chemistry--A European Journal Communication doi.org/10.1002/chem.202101621 achieved via well-established and inexpensive distillation techniques. In conclusion, BTMP has been employed as a source of *OCF3 radicals in CH trifluoromethoxylation reactions of aromatic compounds. Using either visible light photoredox catalysis or TEMPO as a catalytic electron shuttle, valuable trifluoromethoxylated arenes could be prepared under mild conditions, while direct radical trifluoromethoxylation of underexplored pyridine derivatives was achieved. Given the ready availability of BTMP from inexpensive bulk compounds, we believe these methods could serve as useful routes to OCF3containing building blocks. Acknowledgements The authors thank Dr. Carlo Fasting (FU Berlin) for instruction on advanced chromatographic separation techniques. Financial support from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Project-ID 387284271-SFB 1349 (gefrdert durch die Deutsche Forschungsgemeinschaft (DFG)Projektnummer 387284271-SFB 1349), the European Research Council (ERC, HighPotOx-Grant agreement ID: 818862) and the Fonds der chemischen Industrie (FCI, Sachkostenzuschuss) is gratefully acknowledged. We are also very grateful for the continued support of the Solvay company. We would like to acknowledge the assistance of the Core Facility BioSupraMol supported by the DFG. Open access funding enabled and organized by Projekt DEAL. Scheme 5. CH Trifluoromethoxylation of pyridines with BTMP. 19F NMR yields, isolated yields in parentheses. A: TEMPO catalysis conditions ((Substrate (5 eq.), BTMP (1 eq., 0.5 mmol), TEMPO (25 mol%), Na2CO3 (1 eq.), 16 h, rt, B: photocatalysis conditions (see Scheme 2). a 6 mmol scale. b 3 mmol scale. c 0.5 mmol scale. d neat at 30 C. e in MeCN (2.0 M). f in MeCN (0.4 M). g in MeCN (0.2 M). h 6 h. pyridine motif likely inhibits undesired direct electron transfer steps, which are thought to take place between electron rich aromatics and OCF3 reagents.[17] The product regioisomers could be separated from the unreacted substrate and from each other via normal-phase column chromatography while, in no case, were bis(trifluoromethoxy) side-products resulting from double addition observed by GC-MS.[18] As chromatography is unattractive for large scale applications, differential scanning calorimetry (DSC) analysis was performed to assess the potential isolation of each regioisomer by fractional distillation. As shown in Scheme 5, a significant decrease in the boiling point was observed upon trifluoromethoxylation (up to 45.7 C for 5 fa), while for most examples, meaningful differences in the boiling points of each product regioisomer were measured (up to 33 C for 5 ea and 5 eb). These results suggest that radical trifluoromethoxylation with BTMP could prove useful as a practical one-step method for the preparation of (trifluoromethoxy)pyridine building blocks with final product isolation being Keywords: (hetero)arenes fluorine photocatalysis TEMPO trifluoromethoxylation [1] a) P. Jeschke, ChemBioChem 2004, 5, 570-589; b) K. L. Kirk, J. Fluorine Chem. 2006, 127, 1013-1029; c) K. Mller, C. Faeh, F. Diederich, Science 2007, 317, 1881-1886; d) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320-330; e) B. Manteau, S. Pazenok, J.-P. Vors, F. R. Leroux, J. Fluorine Chem. 2010, 131, 140-158; f) R. Berger, G. Resnati, P. Metrangolo, E. Weber, J. Hulliger, Chem. Soc. 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Ed. 2020, 59, 21475-21480; Angew. Chem. 2020, 132, 21659-21664; d) Z. Deng, M. Zhao, F. Wang, P. Tang, Nat. Commun. 2020, 11, 2569; e) A. V. Nyuchev, T. Wan, B. Cendn, C. Sambiagio, J. J. C. Struijs, M. Ho, M. Gulas, Y. Wang, T. Nol, Beilstein J. Org. Chem. 2020, 16, 1305-1312; Review article: f) J. W. Lee, K. N. Lee, M.-Y. Ngai, Angew. Chem. Int. Ed. 2019, 58, 11171-11181; Angew. Chem. 2019, 131, 11289-11299; For a related difluoromethoxylation reaction, see: g) J. W. Lee, W. Zheng, C. A. Morales-Rivera, P. Liu, M.-Y. Ngai, Chem. Sci. 2019, 10, 3217-3222; For a related radical trifluoromethoxylation of alkynes, see: h) F. Wang, Y. Guo, Y. Zhang, P. Tang, ACS Catal. 2021, 11, 3218-3223. [7] a) F. Swarts, Bull. Soc. Chim. Belg. 1933, 102-113; b) R. S. Porter, G. H. Cady, J. Am. Chem. Soc. 1957, 79, 5628-5631; c) R. S. Porter, G. H. Cady, (USA), US3230264 A, 1966; d) R. G. Syvret, B. A. Allentown, G. A. Cooper, (Inc. Air Products and Chemicals), EP1757581B1, 2006; e) J. H. Nissen, T. 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Leuenberger, F. R. Leroux, Eur. J. Org. Chem. 2010, 2010, 6043-6066. [14] A. Liang, S. Han, Z. Liu, L. Wang, J. Li, D. Zou, Y. Wu, Y. Wu, Chem. Eur. J. 2016, 22, 5102-5106. [15] 2-(Trifluoromethoxy)pyridine substrates were previously prepared using reagent D (see Ref. [6d]), while a small selection of 3-(trifluoromethoxy) pyridines were obtained using reagent A (see Ref. [5]). 2-(Trifluoromethoxy)pyridines have also been synthesized upon migration of the OCF3 group. See, for example: a) K. N. Hojczyk, P. Feng, C. Zhan, M. Y. Ngai, Angew. Chem. Int. Ed. 2014, 53, 14559-14563; Angew. Chem. 2014, 126, 14787-14791; b) P. Feng, K. N. Lee, J. W. Lee, C. Zhan, M.-Y. Ngai, Chem. Sci. 2016, 7, 424-429. [16] J. D. Scott, A. W. Stamford, E. J. Gilbert, J. N. Cumming, U. Iserloh, J. A. Misiaszek, G. Li, (Schering Corporation), WO 2011/044181 Al, 2011. [17] This undesired reaction was previously discussed for anisole by Ngai and co-workers, see the Supporting Information of Ref. [5]. [18] In the reaction of 4 c, 2-fluoro-5-(trifluoromethoxy)isonicotinonitrile was also observed (1H NMR, 19F NMR, GC-MS) as a minor side-product (see the Supporting Information). Manuscript received: May 7, 2021 Accepted manuscript online: June 7, 2021 Version of record online: July 2, 2021 Chem. Eur. J. 2021, 27, 11554 - 11558 www.chemeurj.org 11558 2021 The Authors. Published by Wiley-VCH GmbH