Organic Chemistry Fro N Tiers

ORGANIC CHEMISTRY FRO N TIERS

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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

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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 F 25 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. Isolated yield 14 0 54 based on the alkene. c K2S2O8 (1 equiv) was used as the acetone/H2O (1:1) 55 additive. a Conditions: A-1a (0.2 mmol), Selectfluor (0.4 mmol), 56 acetone, H2O (2 mL), Ag(I) source, organic solvent and o b 57 of electron-rich mono-substituted alkenes underwent F- additive if applicable, 50 C, 12 h. Isolated yield based on A- 1a. c Water (1.5 mL) was used. 58 ATRA to afford the expected products 1a–1f in Organic 59 satisfactory yields. Styrenes were also excellent substrates 60 for the condensation, as exemplified by the synthesis of 1g The above excellent performance of acetoacetates and in 90% yield. Di-substituted alkenes also exhibited a high 1,3-diketones urged us to examine the possibility of using reactivity (1h–1l). Functional groups such as ester, ordinary ketones such as acetone in carbofluorination. The

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1 2 condensation of acetone with alkene A-1a and Selectfluor a Reaction conditions: alkene (2 mmol), Selectfluor (4 mmol, 3 under the above conditions gave only a trace amount of 2 equiv), AgOAc (0.2 mmol, 10 mol %), NaOAc (6 mmol), o b 4 acetone (20 mL), H2O (20 mL), 50 C, 12 h. Isolated yield the expected carbofluorination product 2a. We then went c 5 based on the alkene. AgOAc (20 mol %) and H2O (10 mL) on to optimize the reaction conditions (Table 1). When were used. d Selectfluor (3 equiv) and AgOAc (15 mol %) were 6 acetone was directly used as the co-solvent, all the alkene used. 7 A-1a was consumed and 2a was isolated in 17% yield 8 proceeded to give the product 2a in 30% yield (entry 11, (entry 4, Table 1). Switching AgNO3 to AgOAc did not 9 increase the product yield (entry 5, Table 1). However, a Table 1). While the role of NaOAc is not clear at this 10 large portion (~ 60%) of alkene A-1a was now recovered. moment, it might act as a weak base to absorb the acid 11 This unusual difference prompted us to check the effect of generated during the reaction. KOAc showed an effect 12 NaOAc. Indeed, with 3 equivalents of NaOAc as the similar to NaOAc (entry 13, Table 1). However, the 13 additive, the product yield was increased to 90% (entry 8, reaction was significantly retarded when NaOAc was 14 Table 1). The reaction also proceeded smoothly when the replaced by NaHCO3 (entry 14, Table 1). 15 catalyst loading was lowered to 10 mol % (entry 9, Table The above optimization revealed that the F-ATRA with 16 1). Notably, with water as the only solvent and 3 acetone proceeded nicely under much milder conditions. 17 The procedure was particularly advantageous in that no 18 equivalents of acetone as the substrate, the reaction also other organic solvent was required and the condensation Manuscript 19 Scheme 3. Carbofluorination of Alkenes with was conducted under almost neutral conditions. As a result, 20 Acetone the carbofluorination enjoyed a broad substrate scope and 21 wide functional group compatibility, as demonstrated in 22 Scheme 3. Mono-, di- and even tri-substituted alkenes 23 R3 AgOAc (cat) F were all nice acceptors, furnishing the corresponding 24 O SelectFluor O R3 + R2 2 products 2, 3 and 4, respectively. Various functional 25 NaOAc, H O R 1 2 R1 groups were well tolerated, including labile free R o 26 50 C, 12 h a, b 2-5,yield carboxylic acid, unprotected hydroxyl group and primary 27 F alkyl bromide (in 2b, 2j and 2f), a unique characteristic of 28 2a (X = NPhth), 88%; 2b (X = OH), 90%

O X ATRA reactions. In addition, the reactions were scalable Accepted 29 2c (X = OTs), 79%; 2d (X = OBz), 97% 2e (X = NHBs), 86%; 2f (X = Br), 95% and the products could be easily obtained in gram scale 30 31 F F without any decrease in efficiency. Note that the reactions O O 32 2g,81% 2h, 90% were not only efficient but also highly regioselective. The 33 O condensation could also be stereoselective, as indicated by F the synthesis of bicyclic compound 5. This method could 34 X c O 2i (X = OBn), 90%; 2j (X = OH), 56% be utilized in direct modification of complex molecules. 35 2k (X = OEt), 78%; 2l (X = NHBn), 69% 36 O For example, the condensation of carbohydrate 6 with F F CO2Et acetone and Selectfluor gave the product 7 in 72% yield 37 O Ph O 2n, 75% 38 2m, 85% CO2Et (Equation 1). In another case, steroid 8 underwent 39 stereoselective carbofluorination to give 9 as the only Frontiers F 40 F 3ac (X = OEt), 85% stereoisomer isolated (Equation 2). O O X d Ph 2o, 46% 3b (X = 41 Me 42 O NHC6H4-CN-p), 78% O F O O 43 O O O 3cd (R = (CH ) Ph), 82%; 3dc (R = TBDPS), 87% O AgOAc (20 mol %) 44 OR 2 3 O O Selectfluor (2 equiv) Me 3ed (R = COC H -CN-p), 83% O 6 4 NaOAc (3 equiv) O 45 O F F O F 46 acetone/H2O O O Ts O CO Et o 47 N 3fd,75% 2 3gc, 75% O 50 C, 12 h O Me Me (1) 48 Boc 6 72% (50 : 50) 7

49 F F

Chemistry O OTBDPS O c 50 3hd, 93% 3i , 75% Me Me F 51 CO2Et same O H as above H 52 F CO2Me F 53 O O H H 3jc, 78% Cl 3kd,90% 50% H H 54 Me Cl AcO (2) 8 AcO 9 55 F F 56 d c O 3l , 93% O 4a (X = OTBDPS), 52% The carbofluorination could also be extended to the use 57 (79 : 21) 4bc (X = NPhth), 48% tBu of other ordinary ketone such as cycloalkanones and 3- 58 X pentanone, as depicted in Scheme 4. Under the re- Organic 59 F O CO Me optimized conditions, moderate to good efficiency was 60 O 2 c 4cc, 52% 5 ,76% typically observed. Nevertheless, direct α-fluorination of (93 : 7) OBz F CO2Me ketones could now be detected in small extents,

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1 2 presumably due to the decreased electrophilicity of α-keto O F 3 radicals (vide infra). F NaH Ac EtO C 4 EtO C OTs THF or DMF 2 n 2 n 5 1d, 1b, 1e 11 (n = 1), 80% (74:26) 6 Scheme 4. Carbofluorination of Alkenes with Simple 12 (n = 2), 78% (82:18) 7 Ketones 13 (n = 3), 74% (63:37) Me F 8 AgOAc (cat) F R R R3 R R F tBuOK, THF 9 SelectFluor 3 O R CO2Et 10 + R2 2 Me O KOAc, H O/HOAc R 68% 1 2 O R1 11 O R o 3a 14 50 C, 12 h a, b OH 12 10, yield Me F F F 13 n F CO2Me tBuOK, THF 14 NPhth NPhth O O O 15 O Me 83% 10a (n = 1), 42%; 10b (n = 2), 40% 10d,36% 16 10c (n = 3), 28% 3j OH 15 17 F F O O Me F 18 Cl F TsOH, PhMe OAr Manuscript O O 19 O Me Cl NHTs EtO2C 81% N Me EtO2C Ts 20 10e (Ar = p-Cl-C6H4), 65% 10f, 66% 21 1l 16 F O F CO2Me 22 Ph 1. K CO ,MeOH F O O 2 3 23 O F 2. TsOH, PhMe Me O Me O OAc 24 10g, 53% 10h, 54% EtO2C 66% O 25 EtO2C a 1f 17 26 Reaction conditions: alkene (0.2 mmol), ketone (2 mmol), Selectfluor (0.4 mmol), AgOAc (0.04 mmol), KOAc (0.6 Me F 27 o b O 1. Pd/C, H2 mmol), H2O (1 mL), HOAc (0.4 mL), 50 C, 12 h. Isolated F 2. TsOH, CH Cl 28 yield based on the alkene. If applicable, the products were 2 2 Accepted 29 obtained as ~1:1 mixture of stereoisomers. EtO2C OBn Me 54% O O 30 1h O 18 31 32 1. NaBH4/THF Me Scheme 5. Conversion of Carbofluorination Products F 2. NaOH/MeOH F 33 O 3. Yamaguchi's to Fluorinated Carbo- and Heterocycles CO Et 34 Me 2 35 68% O O 3a(50:50) 19 36 37 The broad substrate scope and excellent functional 38 group compatibility of carbofluorination demonstrated 39 above allow the convenient access to divergent and Frontiers 40 polyfunctional organofluorine compounds, which should 41 serve as versatile synthetic intermediates. For example, 42 monofluorinated carbo- and heterocycles18 can be easily 43 prepared from the carbofluorination products (Scheme 5). 44 Thus, fluorinated carbocycles 11–13 were readily prepared 45 in one step from compound 1d, 1b and 1e, respectively, 46 via intramolecular nucleophilic substitution. 4- 47 Fluorocyclohexanones 14 and 15 were produced from 3a 48 and 3j via base-promoted Dieckmann condensation. 49 Cyclic enamine 16 and enol ether 17 were readily obtained Chemistry 50 from 1l and 1f via dehydration. Deprotection of benzyl 51 ether 1h followed by ester exchange afforded 7-membered 52 lactone 18 as a single stereoisomer. Reduction of ketone 53 3a followed by hydrolysis and subsequent Yamaguchi 54 lactonization16 produced 8-membered lactone 19. It is 55 conceivable that more new fluorinated cyclic compounds 56 can be reached via similar strategies. Note that these cyclic 57 compounds are also valuable building blocks in the

58 Organic synthesis of more complex fluorinated molecules. 59 60

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1 F 2 AgOAc (20 mol %) and the efficiency of carbofluorination is lowered, 3 Selectfluor (2 equiv) O consistent with our experimental observations. Note that 4 NaOAc (3 equiv) (3) the proposed mechanism is in close similarity with that of 3b, 5 5 acetone/H2O transition-metal-asisted Cl-ATRA, thus justifying its EtO C CO Et o EtO2C CO2Et 6 2 2 50 C, 12 h classification as F-ATRA processes. 20 21, 46% 7 (81:19) 8 AgOAc (20 mol %) O Cl 9 N Selectfluor (3 equiv) R 10 NaOAc (3 equiv) O F N (4) 11 F F acetone/H2O C10H21 Ag(I) C10H21 O 12 22 50 oC, 12 h 23,59% Cl 13 (Z : E = 10:90) R N N 14 15 R F Ag(II) F Ag(III) 16 O 17 18 O + O Manuscript -H+ 19 10, 12c, 19, 20 20 As indicated above, a radical fluorination mechanism might be involved in the carbofluorination of 21 Figure 1. Proposed mechanism of carbofluorination. 22 unactivated alkenes. A more direct evidence was the 23 reaction of 1,6-diene 20 with acetone in which the cyclization product 21 was isolated in 46% yield along 24 Conclusion 25 with the recovery of diene 20 in 23% yield (Eq 3). In conclusion, we have successfully developed the 26 Furthermore, vinylcyclopropane 22 was designed as the 21 silver-catalyzed formal F-ARTA reactions with the 27 radical probe. The reaction of 22 with acetone under the 28 above optimized conditions (Scheme 2) led to the ring- employment of ketones and Selectfluor as the substitute 29 opening product 23 in 59% yield along with the recovery for α-fluoroketones, allowing the three-component Accepted 30 of 22 in 20% yield (Eq 4). These experiments provide condensation of unactivated alkenes, ketones and 31 solid evidence for the intermediacy of α-carbonyl radicals Selectfluor in aqueous solution under mild conditions. The 32 in carbofluorination. To gain more insight into the results significantly expand the scope of radical 33 mechanism, the following experiments were carried out. fluorination. Furthermore, they offer a new way of 34 When Selectfluor was replaced by the combination of thinking for the practice of ATRA reactions, which should find important implication both in radical chemistry and in 35 K2S2O8 (2 equiv) and KF (2 equiv), the reaction of acetone 36 with alkene A-1a gave the addition–hydrogenation organofluorine chemistry. 37 product 24 in 68% yield while no carbofluorination 38

product 2a could be detected (Eq 5). This implied that Frontiers 39 Ag(II)F alone was unlikely to initiate the carbofluorination. Experimental Section 40 When AgOAc was switched to divalent silver–1,10- Typical Procedure for Silver-Catalyzed 41 phenanthroline complex Ag(Phen) S O , the reaction of 2 2 8 Carbofluorination of Unactivated Alkenes with Active 42 acetone with A-1a and Selectfluor under various 43 Methylene Compounds. N-(Pent-4-en-1-yl)phthalimide conditions also led to the formation of 24 rather than 2a, 44 (A-1a, 215 mg, 1.0 mmol), AgNO (34 mg, 0.20 mmol) indicating the adduct radicals could not directly abstract 3 45 and Selectfluor (706 mg, 2.0 mmol) were placed in a fluorine atoms from Selectfluor. 46 Schlenk tube under nitrogen atmosphere. Dichloromethane A plausible mechanism was thus proposed based on 47 10 (2.5 mL), water (7.5 mL), acetic acid (2.5 mL) and ethyl the above results as well as our previous findings. As 48 acetoacetate (0.38 mL, 3.0 mmol) were added successively shown in Figure 1, the interaction of Ag(I) with 49 at room temperature. The reaction mixture was gently Selectfluor generates the Ag(III)–F intermediate, Chemistry 50 refluxed (at ~ 50 oC) with stirring for 12 h. The resulting presumably via oxidative addition. The single electron 51 mixture was cooled down to room temperature and transfer between acetone and Ag(III)–F gives Ag(II)–F 52 extracted with CH Cl (3 × 20 mL). The organic phases and acetonyl radical cation. Deprotonation of acetonyl 2 2 53 were combined and dried over anhydrous Na SO . After radical cation affords the electrophilic α-carbonyl radical, 2 4 54 the removal of solvent under reduced pressure, the crude which adds selectively to electron-rich C=C bond to 55 product was purified by column chromatography on silica provide the adduct radical as a nucleophilic alkyl radical. 56 gel with hexane/ethyl acetate (5:1, v:v) as the eluent to 57 The subsequent fluorine atom transfer from Ag(II)–F to give the pure product 1a as a colorless oil. Yield: 338 mg

58 the adduct radical leads to the carbofluorination product Organic (93%). Ketone 1a is in equilibrium with its enol form in 59 and regenerates the catalyst Ag(I), which enters into the CDCl (in ~ 86:14 ratio at 20 oC), as indicated by 1H NMR. 60 next catalytic circle. This mechanism well explains the 3 1H NMR (400 MHz, CDCl ) δ 7.82-7.84 (m, 2H), 7.71- umpolung of ketones. Moreover, when α-keto radicals 3 7.73 (m, 2H), 4.40-4.61 (m, 1H), 4.17-4.27 (m, 2H), 3.66- bear an alkyl substituent, they become less electrophilic 3.75 (m, 3H), 2.00-2.52 (m, 5H), 1.59-1.89 (m, 4H), 1.24-

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1 13 2 1.30 (m, 3H); C NMR (100 MHz, CDCl3): δ 202.3/202.2, [5] (a) T. Pintauer, Eur. J. Inorg. Chem. 2010, 2449-2460; (b) K. 3 169.2/169.0, 168.2, 133.9, 131.9, 123.1, 91.6/91.5 (2d, J = Severin, Curr. Org. Chem. 2006, 10, 217-224; (c) A. J. Clark, 4 Chem. Soc. Rev. 2002, 31, 1-11. 167.5 Hz), 61.5, 55.5/55.2 (2d, J = 2.3 Hz), 37.3, [6] (a) R. E. Banks, S. N. Mohialdin-Khaffaf, G. S. Lal, I. Sharif and 5 33.3/33.1 (2d, J = 19.3 Hz), 32.5 (d, J = 20.5 Hz)/32.4 (d, R. G. Syvret, J. Chem. Soc., Chem. Commun. 1992, 595-596; 6 J = 20.0 Hz), 29.5/29.0, 24.2 (d, J = 1.5 Hz)/24.1 (2d, J = (b) R. P. Singh and J. M. Shreeve, Acc. Chem. Res. 2004, 37, 7 19 1.2 Hz), 13.9; F NMR (282 MHz, CDCl3): δ -182.9/- 31-44; (c) P. T. Nyffeler, S. G. Durón, M. D. Burkart, S. P. 8 183.5 (2m, 1F); IR (film): υ (cm-1) 1772, 1713; ESI-MS: Vincent and C.-H. Wong, Angew. Chem. Int. Ed. 2005, 44, 192- 9 + 212. (m/z) 386.1 (M +Na); HRMS calcd for C19H22FNNaO5 10 [7] (a) K. Müller, C. Faeh and F. Diederich, Science 2007, 317, (M+Na): 386.1374, found: 386.1361. 1881-1886; (b) D. O’Hagan, Chem. Soc. Rev. 2008, 37, 308- 11 Typical Procedure for Silver-Catalyzed 319; (c) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, 12 Chem. Soc. Rev. 2008, 37, 320-330; (d) K. L. Kirk, Org. 13 Carbofluorination of Unactivated Alkenes. N-(Pent-4- Process Res. Dev. 2008, 12, 305-321. 14 en-1-yl)phthalimide (A-1a, 431 mg, 2.0 mmol), AgOAc [8] (a) P. W. Miller, N. J. Long, R. Vilar and A. D. Gee, Angew. 15 (34 mg, 0.20 mmol), Selectfluor (1.41 g, 4.0 mmol) and Chem. Int. Ed. 2008, 47, 8998-9033; (b) S. M. Ametamey, M. 16 sodium acetate (489 mg, 6.0 mmol) were placed in a Horner and P. A. Schubiger, Chem. Rev. 2008, 108, 1501-1516. Schlenk tube under nitrogen atmosphere. Water (20 mL) [9] For the latest selected reviews, see: (a) V. V. Grushin, Acc. 17 Chem. Res. 2010, 43, 160-171; (b) T. Furuya, J. E. M. N. Klein 18 and acetone (20 mL) were then added successively at and T. Ritter, Synthesis 2010, 42, 1804-1821; (c) T. Furuya, A. Manuscript 19 room temperature. The reaction mixture was then stirred at S. Kamlet and T. Ritter, Nature 2011, 473, 470-477; (d) T. Liang, o 20 50 C for 12 h. The resulting mixture was cooled down to C. N. Neumann and T. Ritter, Angew. Chem. Int. Ed. 2013, 52, 21 room temperature and extracted with CH2Cl2 (3 × 50 mL). 8214-8264. 22 The organic phases were combined and dried over [10] (a) F. Yin, Z. Wang, Z. Li and C. Li, J. Am. Chem. Soc. 2012, 134, 10401-10404; (b) Z. Li, L. Song and C. Li, J. Am. Chem. 23 anhydrous Na2SO4. After the removal of solvent under Soc. 2013, 135, 4640-4643; (c) C. Zhang, Z. Li, L. Zhu, L. Yu, Z. 24 reduced pressure, the crude product was purified by Wang and C. Li, J. Am. Chem. Soc. 2013, 135, 14082-14085. 25 column chromatography on silica gel with hexane/ethyl [11] For the latest example of oxidative generation of acetonyl 26 acetate (10:1, v:v) as the eluent to give the pure product 2a radicals, see: B. Schweitzer-Chaput, J. Demaerel, H. Engler 27 as a white solid. Mp: 56–58 oC. Yield: 512 mg (88%). 1H and M. Klussmann, Angew. Chem. Int. Ed. 2014, 53, 8737- 8740. 28 NMR (400 MHz, CDCl3): δ 7.73-7.77 (m, 2H), 7.62-7.66 [12] (a) A. D. Dilman, P. A. Belyakov, M. I. Struchkova, D. E. Accepted 29 (m, 2H), 4.35-4.52 (m, 1H), 3.61-3.65 (m, 2H), 2.46-2.57 Arkhipov, A. A. Korlyukov and V. A. Tartakovsky, J. Org. Chem. 30 (m, 2H), 2.07 (s, 3H), 1.45-1.87 (m, 6H); 13C NMR (100 2010, 75, 5367-5370; (b) E. P. A. Talbot, T. A. Fernandes, J. M. 31 McKenna and F. D. Toste, J. Am. Chem. Soc. 2014, 136, 4101- MHz, CDCl3): δ 207.7, 168.3, 133.9, 132.0, 123.1, 92.8 (d, 32 J = 167.0 Hz), 38.7 (d, J = 3.8 Hz), 37.4, 32.4 (d, J = 20.5 4104; (c) H. Wang, L.-N. Guo and X.-H. 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