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Organic Chemistry Fro N Tiers ORGANIC CHEMISTRY FRO N TIERS Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. http://rsc.li/frontiers-organic Page 1 of 7 Organic Chemistry Frontiers 1 2 Formal Fluorine Atom Transfer Radical the substitute for their products (monofluorinated active 3 methylene compounds) (Scheme 1). In view of the 4 Addition: Silver-Catalyzed widespread and growing use7 of organofluorine 5 Carbofluorination of Unactivated compounds in agrochemicals, pharmaceuticals and 6 Alkenes with Ketones in Aqueous materials and the importance of 18F-labeled organic 7 compounds in positron emission tomography (PET),8 this 8 Solution formal F-ATRA process should also be advantageous in 9 that it allows the rapid assembly of cheap and readily 10 a b b *, a,b available substrates and fluorinating reagents into Lin Zhu, He Chen, Zijia Wang, and Chaozhong Li 9 11 polyfunctional fluorinated molecules. Herein we report 12 the silver-catalyzed formal F-ARTA reactions in aqueous 13 a Department of Chemistry, University of Science and Technology solution. 14 b 15 of China, Hefei, Anhui 230026, P. R. China, and Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Scheme 1. ATRA versus Formal ATRA. 16 Lingling Road, Shanghai 200032, P. R. China 17 18 Manuscript 19 ABSTRACT: In this Article, we report the first examples 20 of carbofluorination of unactivated alkenes. Under the 21 catalysis of AgNO3, the reactions of unactivated alkenes 22 with Selectfluor reagent and active methylene compounds such as acetoacetates or 1,3-dicarbonyls in 23 CH2Cl2/H2O/HOAc solution afforded the corresponding 24 three-component condensation products under mild 25 conditions. Furthermore, with the promotion of NaOAc, 26 the AgOAc-catalyzed carbofluorination of various 27 unactivated alkenes with Selectfluor and acetone Results and Discussion 28 proceeded smoothly in aqueous solution at 50 oC. The We recently reported10 that the combination of Accepted 29 carbofluorination was efficient and highly regioselective, catalytic amount of AgNO3 with Selectfluor resulted in the 30 and enjoyed a broad substrate scope and wide functional decarboxylative fluorination of aliphatic carboxylic 31 group compatibility. These formal fluorine atom transfer acids,10a the intramolecular aminofluorination of radical addition reactions provide a convenient entry to 32 alkenes10b and the intermolecular phosphonofluorination 33 structurally divergent, polyfunctional organofluorine 10c compounds as versatile synthetic intermediates. of unactivated alkenes. During the course of these 34 studies, we noted that small amounts of hexane-2,5-dione 35 could be detected by GC-MS in some cases when acetone 36 was used as the co-solvent. This phenomenon implied that 37 Introduction acetonyl radicals might be generated from the oxidation of 38 11 Atom transfer radical addition (ATRA) reactions, acetone by reaction with AgNO3/Selectfluor. If this was Frontiers 39 discovered by Kharasch1 and significantly promoted by the case, electrophilic α-keto radicals might be produced 40 2 Curran and others, have been demonstrated as a versatile and trapped by electron-rich alkenes to give the adduct 41 tool in organic synthesis.3 The most common ATRA radicals as nucleophilic alkyl radicals. The subsequent 42 processes are iodine-atom-transfer in which carbon-iodine 43 fluorination of the adduct radicals would lead to the 44 bonds are added across alkenes or alkynes in the presence carbofluorination products. It should be pointed out that 45 of a radical initiator. A representative example is the only a few examples of intermolecular carbofluorination 46 addition of iodinated active methylene compounds onto were reported and they dealt with activated alkenes such electron-rich alkenes, as shown in Scheme 1, a process as styrenes or enamines.12, 13 47 4 48 driven partically by radical polar effect. Bromine and Thus, N-(pent-4-en-1-yl)phthalimide (A-1a) and ethyl 49 chlorine ATRA reactions have also been developed and acetoacetate that is more prone to oxidation than 14 Chemistry 50 can be catalyzed by a number of transition metal acetone, were used as the model substrates in search of 51 complexes such as copper and ruthenium via transition- optimal reaction conditions (see Table S1 in the 5 52 metal-assisted Cl (or Br)-atom-transfer mechanism. On Supporting Information for details). We were delighted to 53 the other hand, fluorine ATRA reactions are virtually find that, with the catalysis of AgNO3, the reaction of the 54 unknown probably because of the much higher C–F bond two model substrates with Selectfluor proceeded smoothly o 55 dissociation energies. However, if one considers that in CH2Cl2/H2O/HOAc (1:3:1) at reflux (~ 50 C) leading 56 monofluorinated active methylene compounds are to the expected F-ATRA product 1a in 93% isolated yield. 57 typically prepared from the reactions of active methylene Control experiments indicated that AgNO3 was necessary 58 compounds with electrophilic fluorinating reagents such as to initiate the reaction, while other silver(I) salts such as Organic 59 Selectfluor (1-chloromethyl-4-fluoro-1,4- AgOAc showed similar effect. No fluorination took place 60 diazoniabicyclic[2,2,2]octane bis(tetrafluoroborate)),6 it when Selectfluor was switched to N-fluorobis- will become an interesting variant of F-ATRA to use (benzenesulfonyl)imide (NSFI)15. To the best of our directly the combination of the two starting materials as 1 Organic Chemistry Frontiers Page 2 of 7 1 2 knowledge, this is also the first example of intermolecular tosylate, sulfonamide and aryl or alkyl halide, were well 3 carbofluorination of unactivated alkenes. tolerated. Active methylene compounds other than 4 We then moved on to examine the scope and limitation acetoacetates could also be employed for the 5 of this new method. As illustrated in Scheme 2, a number carbofluorination. While the reactions of acetylacetone 6 proceeded sluggishly under the above conditions, they 7 Scheme 2. Carbofluorination of Alkenes with Active were speeded up by the addition of K2S2O8 (1 equiv), 8 Methylene Compounds. furnishing the corresponding products (1o–1q) in high 9 yields. The role of K2S2O8 remains unclear at this 10 moment.16 Cyanoacetate was also a good substrate for the AgNO3 (20 mol%) 11 1 R SelectFluor (2 equiv) E2 F condensation, as proved by the synthesis of 1r in good 12 E1 E2 + 1 yield. On the other hand, malononitrile showed a low R2 1 R 13 CH2Cl2/H2O/HOAc (1:3:1) E 2 o R efficiency and diethyl malonate failed to give any 14 50 C, 12 h a, b 17 1a - 1t, yield carbofluorination product. The results seem to indicate 15 O O that the reactivity of active methylene compounds 16 F F X decreases in the order of acetoacetate > acetylacetone > 17 EtO2C EtO2C OTs 18 cyanoacetate > malononitrile > malonate. 1a (X = NPhth), 93%; 1b (X = OTs), 95% 1d,77% Manuscript 19 1c (X = OBz), 90% Table 1. Optimization of Conditions for the Synthesis 20 O O 21 F F of 2a OAc EtO C 22 EtO2C OTs 2 23 1e,81% 1f,40% 24 O O 25 F F 26 EtO2C OR yield EtO2C Me entrya conditions 27 (%)b Br 1h (R = Bn), 80%; 1i (R = Ac), 70% 28 1g,90% 1j (R = (CH ) Ph), 87% AgNO3 (20 mol %), acetone (3 equiv), 2 3 1c trace Accepted 29 CH2Cl2/H2O/HOAc (1:3:1) O O 30 F F AgNO3 (20 mol %), acetone (3 equiv), 31 Cl NHTs 2c trace EtO2C EtO C CH2Cl2/H2O (1:3) 2 Me 32 Cl AgNO3 (20 mol %), acetone (3 equiv), 33 1k,93% 1l, 67% 3c trace CH3CN/H2O (1:3) 34 O O Ph 35 F F 4 AgNO3 (20 mol %), acetone/H2O (1:1) 17 Cl NPhth 5 AgOAc (20 mol %), acetone/H2O (1:1) 18 36 MeO2C EtO2C 37 Cl 1n, 40% AgOAc (20 mol %), NaOAc (1 equiv), 1m, 89% 6 59 38 acetone/H2O (1:1) Frontiers 39 O O AgOAc (20 mol %), NaOAc (2 equiv), F F 7 75 40 O NPhth O acetone/H2O (1:1) CO Et 41 Me 2 c AgOAc (20 mol %), NaOAc (3 equiv), 1o,89% c 8 90 42 1p,84% acetone/H2O (1:1) 43 O F AgOAc (10 mol %), NaOAc (3 equiv), 44 CN F 9 88 O NPhth acetone/H2O (1:1) 45 EtO2C AgOAc (10 mol %), NaOAc (3 equiv), 46 Br 1r, 55% (63%)c 10 63 1q, 60%c acetone (10 equiv), H2O 47 AgOAc (10 mol %), NaOAc (3 equiv), 48 CN F EtO2C F 11 30 acetone (3 equiv), H2O NPhth NPhth 49 NC EtO2C 2 Chemistry c 12 NaOAc (3 equiv), acetone/H O (1:1) 0 50 1s, 30% 1t,0% AgOAc (10 mol %), KOAc (3 equiv), 51 a Reaction conditions: alkene (1 mmol), ketone (3 mmol), 13 84 acetone/H2O (1:1) 52 Selectfluor (2 mmol), AgNO3 (0.2 mmol), CH2Cl2 (2.5 mL), o b AgOAc (10 mol %), NaHCO3 (3 equiv), 53 H2O (7.5 mL), HOAc (2.5 mL), 50 C, 12 h.
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