Letter pubs.acs.org/OrgLett
Exploring the Reducing Ability of Organic Dye (Acr+‑Mes) for Fluorination and Oxidation of Benzylic C(sp3)−H Bonds under Visible Light Irradiation Ming Xiang, Zhi-Kun Xin, Bin Chen, Chen-Ho Tung, and Li-Zhu Wu* Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry & University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100190, P.R. China S Supporting Information *
ABSTRACT: The excellent oxidizing capability of acridiniumbased organic dye (Acr+-Mes) is fully studied in photoredox catalysis. However, its reducing ability is always considered weak for organic transformation. The reducing ability of Acr+Mes is developed by Selectfluor to achieve effective fluorination and oxidation of benzylic C(sp3)−H bonds under visible light irradiation, which is not available for the direct use of oxidizing ability of excited Acr+-Mes. Mechanistic insights provided strong evidence for the oxidative quenching of Acr+-Mes.
W
ith the rapid development of photoredox catalysis,1 the intriguing acridinium-based organic dye (Acr+-Mes, 9mesityl-10-methylacridinium) has been widely employed in organic synthesis because of its excellent photophysical properties.2 Fukuzumi and Nicewicz used strong oxidizing capability of Acr+-Mes to realize the activation of either C(sp2)−H bond on electron-rich arene or benzylic C(sp3)−H.3 However, such a direct single-electron-transfer (SET)/deprotonation pathway was not efficient toward the more inert C−H bond (Figure 1, path A).4 Subsequently, excited Acr+-Mes (the
In order to implement path C, we need to select an appropriate oxidant [O]. Selectfluor, a commercially available reagent, is not only a well-established mild source of fluorine but is also a strong oxidant for different kinds of fluorination and oxidation reactions.7 Inspired by the pioneering work of Lectka and Baran, who demonstrated that reduction of Selectfluor with copper catalyst would generate an N-radical dication to act as a hydrogen abstractor (HAT) for electronrich C−H bond fluorination or Ritter reaction,8 we envisioned that a photoinduced SET process might be operated between Selectfluor and Acr+-Mes with the generation of N-radical dication. Although the photocatalytic benzylic C−H bond activation has been widely reported, the aid of an α-nitrogen/ oxygen atom next to the benzylic group,9 an electron-donor substituted arene,10 or the high energy ultraviolet light,11 was always required. In the present work, we utilize the new design (Figure 1, path C) to achieve an Acr+-Mes-catalyzed benzylic C−H bond functionalization that expands the scope of substrates to the simplest molecular “ethylbenzene”. Initially, the desired fluorinated product 2a was obtained in 15% yield when Selectfluor was used as the fluorine source in acetonitrile under ambient argon atmosphere with blue LED (λ = 450 ± 10 nm) irradiation for 12 h (Table S1, entry 1). This result encouraged us to make a further optimization. Considering the low solubility of Selectfluor in acetonitrile, the miscible mixture of acetonitrile and water was chosen as the solvent. Examination of a range of different CH3CN/H2O ratios revealed that the best ratio of CH3CN to H2O was 3:1 with respect to reaction efficiency (Table S1, entries 2−4). The same reaction was subsequently attempted using N-fluorobenzenesulfonimide (NFSI), another precedented source of atomic fluorine, but a significantly lower yield (20%) was obtained
Figure 1. Design plan for an Acr+-Mes-catalyzed C−H bond activation.
electron-transfer state, Acr·-Mes·+) was employed to oxidize some anions X− (Cl− or NO3−) to afford some radicals X• (Cl• or NO3•), which could achieve alkane or alcohol oxidation via a hydrogen-atom-abstraction pathway (Figure 1, path B).5 Actually, this route still suffered from very low reaction yield or degradation of Acr+-Mes. In this context, we turn to the intervention of a strong oxidant [O] to explore its reducing ability for activation of more inert C−H bond,6 though the reducing power of excited Acr+-Mes is not very fascinating (Figure 1, path C). © 2017 American Chemical Society
Received: April 26, 2017 Published: May 22, 2017 3009
DOI: 10.1021/acs.orglett.7b01270 Org. Lett. 2017, 19, 3009−3012
Letter
Organic Letters
bonds.12 Finally, a scale-up reaction for 1h (4.5 mmol, 0.74 g) gave 2h in a satisfactory yield (61%). When more reactive substrate “diphenylmethane 3a” was added into the aforementioned system for 12 h, the diaryl ketone 4a was unexpectedly generated in 72% yield by using water as oxygen source (Table S2, entry 1). Various oxidants, such as K2S2O8, NFSI, and BrCCl3, were screened for this transformation, but less favorable yields were obtained (Table S2, entries 2−4), which indicated the final product may be obtained via the formation of fluorodiphenylmethane intermediate. Adjusting the ratio of CH3CN/H2O to 1:1 gave the best yield (77%, Table S2, entry 5). To generalize the oxidation protocol, various diphenylmethane-type substrates were investigated (Scheme 2). Diphenylmethanes bearing electron-
(Table S1, entry 5). Adjusting the amount of Selectfluor was also tested to improve reaction yield; however, less favorable results were obtained (Table S1, entries 6−8). Considering that a chain propagation process was probably involved in the reaction,8c we reduced the reaction time. Fortunately, further increase was achieved, which gave the best yield (82%, Table S1, entry 9). Control experiments confirmed that no reaction occurred in the absence of either the photocatalyst or the visible light source (Table S1, entry 10). Notably, when Ir(ppy)3 or Ru(bpy)3Cl2 was used as the photocatalyst, instead of Acr+-Mes, no desired product was obtained (Table S1, entry 11). With the optimized conditions in hand, a wide range of representative alkylbenzene derivatives were examined to explore the generality of this new fluorination protocol. As summarized in Scheme 1, methyl, methylene, and methine
Scheme 2. Scope of the Benzylic Oxidationa
Scheme 1. Scope of the Benzylic Fluorinationa
a 3 (0.3 mmol), Acr+-Mes (5 mol %) and Selectfluor (2.0 equiv) in CH3CN/H2O (1:1, 4 mL) were irradiated by blue LEDs for 12 h under an argon atmosphere. Isolated yields are shown. b6 mL CH3CN/H2O (1:1) was used as the solvent. a 1 (0.3 mmol), Acr+-Mes (5 mol %), and Selectfluor (2.0 equiv) in MeCN/H2O (3:1, 4 mL) were irradiated by blue LEDs for 1 h under an argon atmosphere. Isolated yields are shown. bDetermined by 19H NMR spectra using C6H5F as an internal standard. cReaction time: 12 h.
donating group, such as t-Bu, Ph, and OMe, showed very high reactivity accomplishing the reaction smoothly (4b−e), just like what was observed in the fluorination reaction. The oxidation reaction was also compatible with F and Cl groups, providing a potential application for further functionalization, while the COOMe group afforded a poor yield (4f−h). Considering that very strong electron-rich substitute was tolerated to generate corresponding product in excellent yield (4e), we speculated that a possible procedure could be excluded, in which the oxidation of substrate to radical cation was followed by nucleophilic attack of water on aromatic ring.13 In addition, substrates with different aryl substitutions were successfully suitable to this transformation (4i,j). Because the Eox value of 1 (+2.27 V for 1a or +2.17 V for 3a vs. SCE in MeCN)14 is higher than the one-electron reduction potential of Acr·-Mes·+ (2.06 V vs SCE in MeCN),15 the reductive quenching process is energetically unfavorable. However, an SET reduction of Selectfluor (Ered = −0.04 V vs. SCE in CH3CN)16 using the excited Acr+-Mes (Eox = −0.57 V vs SCE in CH3CN)15 would be feasible thermodynamically. To gather insights into the SET process between the excited Acr+-Mes and Selectfluor, electron paramagnetic resonance (EPR) experiments were conducted. As shown in Figure 2a, we detected a strong signal from the excited Acr+-Mes, consistent with the Fukuzumi’s report,17 while a new radical signal was
groups could all be fluorinated, and various functional groups on the aromatic ring and side chain were tolerated. For example, the reactivity order Et > i-Pr > Me was observed according to reaction yields (2a−c), which was mainly attributed to the difference of C−H bond dissociation energy (BDE) among these benzylic C−H bonds and the steric repulsion between hydrogen atom abstractor and substrate.11b To our delight, substrates containing a carboxylic ester, acetate, or phthalimide group on the alkyl chain were smoothly converted to the corresponding fluorides in moderate to good yields (2d−f). It should be pointed out that an extended reaction time was needed to improve their conversion. Electron-rich alkylbenzenes (1g,h) were more competent substrates for this reaction in comparison with electrondeficient substrates (1i,j). It took only 1 h for 1g,h to react completely but 12 h for 1i,j to produce relatively low yields. The result can be explained by the theory that the electrophilic N-radical dication preferentially cleaves electron-rich C−H 3010
DOI: 10.1021/acs.orglett.7b01270 Org. Lett. 2017, 19, 3009−3012
Letter
Organic Letters
Figure 3. Support for the involvement of benzylic radical in the fluorination reaction and intermediate investigation for the oxidation reaction.
the benzyl ether may be an intermediate which probably originated from hydrolysis of reactive benzylic fluorides.20 Moreover, the kinetic isotopic effect (KIE) by competition experiments were investigated using a 1:1 mixture of 1a and 1ad2 as substrates (Scheme S1). This significant isotopic effect (kH/kD = 2.3) implied that benzylic C−H bond cleavage probably took place during the rate-limiting step of the reaction. Based on previous reports and these experimental results, a putative mechanism (Scheme 3) is outlined to illustrate
Figure 2. EPR spectra observed after irradiation of an argon-saturated MeCN/H2O solution of Acr+-Mes (3.75 mM) at 233 K for 2 min and then measured at 123 K (a) in the absence and presence of Selectfluor (0.15 M), (b) with increasing measuring temperature to 178 or 233 K without Selectfluor, (c) with increasing measuring temperature to 178 or 233 K with Selectfluor. (d) UV−vis absorption spectra of an argonsaturated MeCN/H2O solution of Acr+-Mes (0.01 mM) and Selectfluor (0.4 mM) under irradiation (from t = 0−360 s).
observed after adding Selectfluor. These phenomena confirmed that Selectfluor could react with the excited Acr+-Mes to produce a new radical. In order to distinguish the latter signal from the former one, we tried to observe their change at different temperature. Obviously, the intensity of former signal decreased with the increase of temperature, whereas no change happened for the latter one (Figure 2b,c). This meant that the original signal of photocatalyst was quenched by Selectfluor and the new signal completely originated from the new radical. We speculated that it would be the N-radical dication.18 Further evidence for the reaction between the excited Acr+-Mes and Selectfluor came from the UV−vis absorption spectra (Figure 2d). When Selectfluor was added to Acr+-Mes under blue LED irradiation, the UV−vis absorbance above 350 nm decreased with time. Subsequently, the time profile of the benzylic fluorination revealed that the reaction was totally inhibited during the “light off” periods (Figure S2). Although it could not rule out the possibility of radical-chain propagation in our system,19 this result evidently supported that the propagating chain reaction was short-lived if there was any. In addition, we directly detected a small amount of byproduct “acetophenone” when treating this reaction in CD3CN/D2O by analyzing 1H NMR spectra of reaction mixture (Figure S3), indicating that benzylic radical would be oxidized to generate benzylic carbocation. On the one hand, diethyl bromomalonate (DEBM) did not give benzylic bromide when Acr+-Mes was utilized as photocatalyst; however, benzylic bromide was generated under our fluorination conditions with DEBM (Figure 3a). It indicated the involvement of benzylic radical in our system. Considering using 5 mol % of photocatalyst for the consumption of substrate, it was necessary that regeneration of Acr+-Mes via oxidation of benzylic radical to initiate the short chain propagation. A control experiment, in which 3a was irradiated for 3 h, furnished a mixture of 4a and benzyl ether with nearly all 3a consumed, and the direct transformation of benzyl ether into 4a was observed after another 3 h (Figure 3b). It revealed that
Scheme 3. Proposed Mechanism
reaction route. Initially, irradiation of organic dye (Acr+-Mes) with visible light leads to the formation of a long-lived electrontransfer state (Acr·-Mes•+)21 which delivers an electron to Selecfluor. The N-radical dication 5 is generated with concomitant formation of Acr+-Mes•+ and F−. Hydrogen abstractor 5 is responsible for the intermolecular benzylic hydrogen abstraction of 1 (or 3) to give benzylic radical 6. Subsequently, 6 directly reacted with Selectfluor, namely radical-chain propagation, affording benzylic fluoride 2. Finally, Acr+-Mes•+ oxidized 6 to generate benzylic carbocation 7, completing the photocatalytic cycle. The generated benzylic carbocation 7 could further undergo nucleophilic addition with F− to produce 2. When the R group is an aryl, hydrolysis of benzylic fluoride would afford benzyl ether, and then it would transform into ketone 4 through photocatalytic oxidation. In conclusion, we have developed the reducing ability of excited Acr+-Mes for effective fluorination and oxidation of benzylic C(sp3)−H bonds. Selectfluor was selected as an oxidant to cooperate with photoredox catalyst Acr+-Mes. EPR and UV−vis absorption spectra supported the formation of N3011
DOI: 10.1021/acs.orglett.7b01270 Org. Lett. 2017, 19, 3009−3012
Letter
Organic Letters
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radical dication via a photoinduced SET between the excited Acr+-Mes and Selectfluor. In contrast to the well-developed strategies (Figure 1, paths A and B), the new platform relying on the reducing ability of Acr+-Mes achieves more inert C−H bond functionalization, which is not amenable to the direct use of oxidizing ability of Acr+-Mes under illumination.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01270. Experimental details and characterization of synthesized compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Bin Chen: 0000-0003-0437-1442 Chen-Ho Tung: 0000-0001-9999-9755 Li-Zhu Wu: 0000-0002-5561-9922 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support for this research from the Ministry of Science and Technology of China (2013CB834804, 2014CB239402, and 2013CB834505), the National Natural Science Foundation of China (21390404 and 91427303), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB17030400), and the Chinese Academy of Sciences is gratefully acknowledged.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b01270 Org. Lett. 2017, 19, 3009−3012
