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Page 1 of 5 Journal Name RSC Advances Dynamic Article Links ► RSC Advances 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. This Accepted Manuscript will be replaced by the edited, formatted and paginated article as soon as this 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. www.rsc.org/advances Page 1 of 5 Journal Name RSC Advances Dynamic Article Links ► Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx ARTICLE TYPE Copper-Catalyzed Trifluoromethylation of Organic Zinc Reagents with Electrophilic Trifluoromethylating Reagent Chang-Sheng Wang, a Haoyang Wang, b Cheng Yao, a,* Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX 5 DOI: 10.1039/b000000x A copper-catalyzed trifluoromethylation of aryl, vinyl and Table 1. Optimization of conditions for copper-catalyzed a alkyl zinc reagent with Togni’s reagent was described. 50 trifluoromethylation of aryl zinc reagent . F3C I O Mechanistic studies indicated that the aryl group is initially ZnI LiCl R CuX/ligand CF3 transferred from zinc reagent to hypervalent iodine to form a R + solvent Ph Ph 10 tri-substituted hypervalent iodine intermediate. Consequent reductive-elimination via a concerted bond-forming step 3 R, R = CH3, 1 R, R = O, 2 and/or radical pathway from this intermediate generates the CF3 Yield trifluoromethylated arenes. entryCuX ligand solvent Manuscript reagent (%)b It is widely recognized and accepted that the introduction of 1 1 CuI Phen THF - 2 1 CuI Phen Et2O - 15 fluorine into small molecules will bring significant beneficial 3 1 CuI Phen Diglyme - effects such as improved pharmacokinetics, increased binding 4 1 CuI Phen 1,4-dioxane - 1 selectivity and enhanced metabolic stability. Thus, incorporation 5 1 CuI Phen ClCH2CH2Cl - of fluorine into drug-like molecules has become an indispensible 6 1 CuI Phen DMF - 7 2 CuI Phen DMF 13 strategy for medicinal chemists in drug design and a daily routine 8 2 CuI - DMF 42 2 20 practice for the discovery of new lead compounds. Among many 9 2 CuCN - DMF 42 10 2 CuCl - DMF 24 fluorinated functional groups, the trifluoromethyl group (CF 3-) is 11 2 CuBr - DMF 36 highly valuable because it might improve the drug’s cellular 12 2 Cu(MeCN) PF - DMF 35 Accepted 3 4 6 membrane permeability, and thus its bioavailability. As a result, 13 2 Cu(OAc)2 - DMF - in the past five years, tremendous efforts have been directed 14 2 CuI - DMF 50 c 15 2 CuI - DMF 61 d 25 towards the development of efficient methods for the formation 16 2 CuI - DMF 72 e of C-CF 3 bond. Consequently, significant advances have been 17 2 CuI - DMF 90 f achieved in transition metal-catalyzed direct trifluoromethylation 18 2 CuI - DMF 90 (64)g of aryl halides, aryl boronic acids or arenes. 4-5 19 2 CuI - DMF 90 h 20 2 CuI - DMF 65 i In 2011, Shen’s group reported a copper-catalyzed a 30 trifluoromethylation of aryl boronic acids using Togni’s reagent 1 Reaction conditions: 4-biphenylzinc reagent (0.1 mmol), Togni’s reagent as the trifluoromethyl source. 4 The reaction was conducted under (0.1 mmol), CuX (10 mol%), ligand (20 mol%), solvent (1.0 mL) at room temperature for 12 h; bYields were determined by 19 F NMR analysis of mild conditions and was compatible with a variety of functional c 55 the crude product using p-Fluorotoluene as an internal standard; 2.0 Advances groups. Inspired by this investigation, we envisaged that an equivalents of reagent 2 was used; d3.0 equivalents of reagent 2 was used; efficient trifluoromethylation method would be developed if a e3.0 equivalents of reagent 2 and 20 mol% of CuI were used; f3.0 equivalents of reagent 2 and 30 mol% of CuI were used; gReaction was 35 zinc reagent could be employed as the nucleophile since zinc conducted for 20 min; Isolated in parentheses; hReaction was conducted at reagent has been demonstrated to be an effective coupling partner o i o 60 0 C; Reaction was conducted at 40 C. in a number of transition metal-catalyzed cross-coupling reactions. 6 Herein, we disclose a copper-catalyzed amount of CuI/1,10-phenanthroline (Phen) in different solvents. RSC trifluoromethylation of aryl 、vinyl and alkyl zinc reagents using To our surprise, the formation of trifluoromethylated biphenyl was observed in less than 10% yield in solvents such as THF, 40 Togni’s reagent 2 as the trifluoromethyl source. Mechanistic studies indicated that the aryl group from the zinc reagent is diethyl ether, diglyme, dioxane, 1,2-dichloroethane or DMF initially transferred to hypervalent iodine to form a tri-substituted 65 (Table 1, entries 1-6). Interestingly, when Togni’s reagent 2 was hypervalent iodine intermediate. Consequent reductive- used, reaction of 4-biphenyl zinc reagent 3 occurred smoothly at elimination via a concerted bond-forming step and/or room temperature to give the desired product in 13% yield after 45 trifluoromethyl radical pathway from this intermediate generates 12 h at room temperature (Table 1, entry 7). The yield was the trifluoromethylated arenes. improved to 42% when the reaction was conducted in the absence We began our study with the reaction of 4-biphenyl zinc 70 of 1,10-phenanthroline (Table 1, entry 8). The effect of the reagent 3 with Togni’s reagent 17-8 in the presence of a catalytic copper salts was then investigated. Nevertheless, the yield of the This journal is © The Royal Society of Chemistry [year] [journal] , [year], [vol] , 00–00 | 1 RSC Advances Page 2 of 5 desired product did not increased significantly when other copper advantage of using zinc reagents is its tolerance of functional salts such as CuCN, CuCl, CuBr, Cu(MeCN) 4PF 6 or Cu(OAc) 2 groups. As illustrated in Table 2, various functional groups such were used (Table 1, entries 9-13). Since it was observed that side as ester, cyano, protected ketone and amide were compatible. products such as trifluoromethane and iodotrifluoromethane were Typically, reaction of Togni’s reagent 2 was proposed to 5 formed in the reaction mixture, it is likely only part of the 40 proceed via a pathway involving an in situ generated CF 3 radical Togni’s reagent was converted to the final product. We then species. 8 To probe if the copper-catalyzed trifluoromethylation of studied the effect of the amount of the Togni’s reagent. The yield zinc reagents proceeds via a radical mechanism, we conducted was improved to 50% and 61%, respectively, when 2.0 or 3.0 two sets of different experiments. In the first experiment, 1.5 equivalents of reagent 2 was used (Table 1, entries 14-15). equivalents of TEMPO, a radical trap, was added to the reaction 10 Furthermore, when 30 mol% of CuI was used, the yield was 45 mixture of 4-biphenyl zinc reagent with Togni’s reagent 2 in the further increased to 90% (Table 1, entry 17). Carefully presence of 30 mol% CuI. The reaction was monitored by 19 F monitoring of the reaction showed that the reaction was NMR spectroscopy and it showed the formation of completed within 20 min at room temperature (Table 1, entry 18). trifluoromethylated TEMPO in 80% yield and the Higher temperature was detrimental to the reaction. The yield trifluoromethylated biphenyl in 16% yield, respectively (Eq 1.). o 15 dropped to 65% when the reaction was conducted at 40 C (Table 50 This result indicated that the copper-catalyzed 1, entry 20). trifluoromethylation reaction was only partially inhibited by Table 2. Scope of copper-catalyzed trifluoromethylation of zinc TEMPO. In the second experiment, we synthesized a zinc reagent reagents with Togni’s reagent. a,b 5 to probe if the radical is indeed involved under the standard F3C I O reaction conditions. Both directed trifluoromethylated product 6a 30 mol % CuI O 55 and cyclized trifluoromethylated products 6b were observed after R ZnI LiCl + R CF3 DMF 20 min at room temperature in 36% and 29% yields, respectively rt, 20 min 3.0 equiv (Eq 2.). These results suggest that the copper-catalyzed trifluoromethylation of aryl zinc reagent might proceed via two Manuscript CF3 CF3 parallel mechanisms: one involved a radical pathway and the CF3 O O 60 other involved a non-radical pathway. Ph R F3C I O O standard reaction NC ZnI LiCl CF conditions 3 O R = Ph, 4a, 64% 4c, 32% 4d, 65% + + TEMPO + N (1) OBn, 4b, 54% Ph Ph OCF3 CF3 CF3 3.0 equiv 1.5 equiv 16% 80% MeO CF3 19 19 Me ( F NMR) ( F NMR) O O F C I O O N 3 standard reaction CF3 ZnI LiCl conditions CF3 O N O + + (2) O O O 4f, 67% 4g, 68% Accepted 4e, 60% 5 3.0 equiv 6a, 36% 6b, 29% Ph 19 19 CF3 ( F NMR) ( F NMR) Ph N CF3 To gain more insight about the mechanism of the reaction, we N Ph CF3 conducted a stoichiometric reaction of CuI with Togni’s reagent 2 4h, 60% 4i, 53% 4j, 57%c (Eq 3.).
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