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DOI: 10.1039/C6NJ00281A (Letter) New J. Chem., 2016, 40, 6564-6567

Visible light-induced monofluoromethylenation of heteroarenes with ethyl bromofluoroacetate†

Wei Yu a, Xiu-Hua Xu a and Feng-Ling Qing *ab
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China. E-mail: flq@mail.sioc.ac.cn
bCollege of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China

Received (in Montpellier, France) 27th January 2016 , Accepted 6th June 2016

First published on 7th June 2016

Abstract

Visible light-induced monofluoromethylenation of benzofurans and benzothiophenes with ethyl bromofluoroacetate was developed. This method provided a convenient access to novel α-fluoro-α-heteroarylesters under mild reaction conditions.

Since Fried and Sabo's discovery that the incorporation of a fluorine atom into a corticosteroid derivative led to valuable enhanced biological activity in 1954,1 fluorinated organic compounds have attracted increasing attention for use in pharmaceuticals and agrochemicals.2 The α-fluoro-α-arylcarboxylic acid moiety is found in many active bioactive compounds3 and has been widely used as a building block in organic synthesis.4 Consequently, lots of efforts have been made in the preparation of α-aryl-α-fluorocarbonyl compounds. There are mainly two strategies for the construction of α-aryl-α-fluorocarbonyl units. The first strategy involves the direct fluorination of α-arylcarbonyl derivatives using nucleophilic5 or electrophilic6 fluorinating reagents. The second strategy involves the condensation reaction of aromatic substrates and fluorine-containing building blocks.7,8 Compared to the direct fluorination strategy, the “building block” strategy has been much less explored despite its potential importance. Recently, Sanford7a as well as Wang and Zhou,7b respectively, reported the SNAr reaction of ortho-fluoronitrobenzenes and 2-fluoromalonates for the preparation of α-aryl-α-fluoroesters (Scheme 1a). Palladium-8a,b and nickel-catalyzed8c cross-coupling reactions of aromatic substrates and fluorine-containing building blocks have provided an efficient strategy to incorporate monofluoromethylene units into aromatic compounds (Scheme 1b). However, both of the methods require the use of prefunctionalized aromatic substrates. The direct monofluoromethylenation of aryl C–H bonds remains a big challenge.
image file: c6nj00281a-s1.tif
Scheme 1 Monofluoromethylenation of (hetero)aromatic compounds.

Recently, visible light photoredox catalysis has emerged as an efficient and eco-friendly tool in organic synthesis9 and has been applied in the fluoroalkylation of organic compounds.10 In 2013, we reported a mild and versatile approach for the direct introduction of an ethoxycarbonyldifluoromethyl group into heteroarenes with ethyl bromodifluoroacetate via visible light photocatalysis.11 On the basis of that work, we anticipated that a similar transformation with ethyl bromofluoroacetate might allow for the direct introduction of the ethoxycarbonylmonofluoromethyl group into heteroarenes. In continuation of our research interest in visible light-induced fluoroalkylation reactions,10f,t,w,11 herein we describe the reactions of benzofurans and benzothiophenes with ethyl bromofluoroacetate under visible light photoredox conditions (Scheme 1c). This reaction provides a convenient approach to the synthesis of novel α-fluoro-α-heteroarylesters.

Initially, we investigated the model reaction of benzofuran 1a with ethyl bromofluoroacetate using blue LEDs as the source of visible light (Table 1). Among the commonly used photocatalysts, only fac-Ir(ppy)3 could promote the reaction giving the desired product 2a in 55% yield, and no reaction occurred in the presence of Ru(bpy)3Cl2·6H2O, methylene blue, or eosin Y (entries 1–4). Other iridium photocatalysts including [Ir(ppy)2Cl]2 and [Ir(dtbbpy)(ppy)2][PF6] were found to be less effective than fac-Ir(ppy)3 (entries 5 and 6). To increase the yield, various inorganic and organic bases including K2CO3, K3PO4, KOAc, t-BuONa, DBU, and DIPEA were tested (entries 7–12). However, none of them gave higher yield. Further screening of different solvents disclosed that DMF, DCM, and THF gave the desired product in slightly lower yields than MeCN (entries 13–15). To our delight, when the reaction was performed in DMF/H2O, the yield of 2a was improved to 74% (entry 16). It is noteworthy that this optimized yield is much higher than the one obtained in the coupling reaction of benzofuran-2-ylboronic acid with ethyl bromofluoroacetate.8b

Table 1 Optimization of reaction conditionsa

image file: c6nj00281a-u1.tif
Entry Photocat. Base Solvent Yieldb (%)
a Reaction conditions: 1a (0.1 mmol), ethyl bromofluoroacetate (0.2 mmol), photocat. (0.005 mmol), base (0.2 mmol), solvent (1.0 mL), visible light, rt, under N2, 12 h. b Yields determined by 19F NMR spectroscopy using fluorobenzene as an internal standard.
1 Ru(bpy)3Cl2·6H2O K2HPO4 MeCN 0
2 fac-Ir(ppy)3 K2HPO4 MeCN 55
3 Methylene Blue K2HPO4 MeCN 0
4 Eosin Y K2HPO4 MeCN 0
5 [Ir(ppy)2Cl]2 K2HPO4 MeCN 29
6 [Ir(dtbbpy)(ppy)2][PF6] K2HPO4 MeCN 12
7 fac-Ir(ppy)3 K2CO3 MeCN 43
8 fac-Ir(ppy)3 K3PO4 MeCN 52
9 fac-Ir(ppy)3 KOAc MeCN 23
10 fac-Ir(ppy)3 t-BuONa MeCN 12
11 fac-Ir(ppy)3 DBU MeCN 21
12 fac-Ir(ppy)3 DIPEA MeCN 13
13 fac-Ir(ppy)3 K2HPO4 DMF 54
14 fac-Ir(ppy)3 K2HPO4 DCM 46
15 fac-Ir(ppy)3 K2HPO4 THF 49
16 fac-Ir(ppy)3 K2HPO4 DMF/H2O 74

With the optimized reaction conditions in hand, we next examined the substrate scope of the visible light-promoted direct monofluoromethylenation of heteroarenes (Table 2). A variety of benzofurans 1a–s were employed to give the corresponding 2-monofluoromethylenated products 2a–s in moderate to excellent yields. The selective formation of 2-substituted isomers is probably due to the generation of a more stable benzylic radical as an intermediate. Different functional groups including ethers, esters, and nitriles were well tolerated. Notably, substrates bearing fluoro, chloro, and bromo substituents on the arene rings are also compatible, thus providing opportunities for additional transformations (1m–1q). With substrates (1r and 1s) containing electron-withdrawing groups, the desired products were isolated in low yields. It is noteworthy that the reaction could be extended to benzothiophenes 1t and 1u, furnishing products 2t and 2u in moderate yields, respectively. The bromofluoromethylenation of indole 1v gave the desired product 2v in 47% yield. However, the electron-rich arene 1w displayed poor reactivity, with only 22% of the product being obtained. In the cases of furan and thiophene, low conversion was observed.

Table 2 Substrate scope of photocatalytic monofluoromethylenation of heteroarenesa

image file: c6nj00281a-u2.tif
a Reaction conditions: 1 (0.5 mmol), ethyl bromofluoroacetate (1.0 mmol), fac-Ir(ppy)3 (0.025 mmol), K2HPO4 (1.0 mmol), DMF/H2O (5.0 mL), visible light, rt, under N2, 12 h, isolated yields.
image file: c6nj00281a-u3.tif

Finally, the control experiments were carried out to gain insights into the reaction mechanism. No reaction took place in the absence of visible light or fac-Ir(ppy)3, and the addition of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), a known radical scavenger, could totally inhibit the reaction. Based on the above results and the reported work,10a,12 a plausible reaction mechanism was proposed as in Scheme 2. Initially, the irradiation of visible light excited fac-IrIII(ppy)3 to fac-IrIII(ppy)3*. Then, a single-electron-transfer (SET) from fac-IrIII(ppy)3* to ethyl bromofluoroacetate generated the radical intermediate A, which was subsequently added to benzofuran 1 for the formation of radical intermediate B. Intermediate B was then oxidized to cation intermediate C, which underwent deprotonation affording the final product 2.


image file: c6nj00281a-s2.tif
Scheme 2 Proposed reaction mechanism.

In conclusion, we have developed a visible light-promoted monofluoromethylenation of heteroarenes with ethyl bromofluoroacetate. This protocol does not require prefunctionalization of the heteroaromatics and proceeds under mild reaction conditions, which makes it attractive in the preparation α-fluoro-α-heteroarylcarbonyl compounds. The investigation of the present method in the synthesis of biologically active compounds is in progress.

Experimental section

General procedure for the photocatalytic monofluoromethylenation of heteroarenes

A 50 mL Schlenk flask equipped with a rubber septum and a magnetic stir bar was charged with fac-Ir(ppy)3 (16.4 mg, 0.025 mmol, 5 mol%), K2HPO4 (174.1 mg, 1.0 mmol, 2.0 equiv.), ethyl bromofluoroacetate (184.9 mg, 1.0 mmol, 2.0 equiv.), and heteroarene (0.5 mmol, 1.0 equiv.). DMF (1.0 mL) and H2O (4.0 mL) were added to the mixture. Then, the reaction mixture was degassed three times by the freeze–pump–thaw procedure. The flask was placed at a distance of 2 cm from the blue LEDs. The mixture was stirred under a nitrogen atmosphere and irradiated by blue LEDs for 12 h. After the reaction was complete, the reaction mixture was extracted by Et2O, and the combined organic phase was dried over anhydrous Na2SO4. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel to give the corresponding product.

Acknowledgements

We thank the National Natural Science Foundation of China (21272036, 21332010 and 21421002) and the National Basic Research Program of China (2012CB21600) for financial support.

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures and analytical data for all new compounds. See DOI: 10.1039/c6nj00281a
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