Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. 2017, 19, 5501-5504
Visible-Light-Enabled Decarboxylative Mono- and Difluoromethylation of Cinnamic Acids under Metal-Free Conditions Wei-Ke Tang,† Yi-Si Feng,*,†,§ Zhuo-Wei Xu,† Zhi-Fei Cheng,† Jun Xu,‡ Jian-Jun Dai,‡ and Hua-Jian Xu*,†,‡ †
Anhui Province Key Laboratory of Advance Catalytic Materials and Reaction Engineering, School of Chemistry and Chemical Engineering, and ‡School of Biological and Medical Engineering, Hefei University of Technology, Hefei 230009, P. R. China § Anhui Provincial Laboratory of Heterocyclic Chemistry, Maanshan 243110, P. R. China S Supporting Information *
ABSTRACT: Several new mono- and difluoromethylation reactions of cinnamic acids using an Eosin Y catalytic system are reported. An efficient alkene fluoromethylation of α,β-unsaturated carboxylic acids was accomplished under ambient temperature and metal-free conditions, with a wide range of functional group tolerance. A mechanism that involves a radical process is proposed for this reaction.
Scheme 1. Decarboxylative Fluoromethylation of α,βUnsaturated Carboxylic Acids
A
llylic motifs have been found in many bioactive compounds and drugs, and compounds with a fluorine atom at the α position of an allylic moiety, allyl fluorides, exhibited significantly enhanced bioactivity compare to their parent compounds, as shown in Figure 1.1 Furthermore, allyl
Figure 1. Examples of bioactive allyl fluorides.
fluorides have served as versatile intermediates in the synthesis of a large number of fluorinated compounds.2 Thus, a catalytic method to form mono- or difluoromethylated allylic compounds under mild conditions with simple and cheap fluorine sources is very valuable and provides an important tool for synthetic and medicinal chemistry.3 In the past few years, transition-metal-mediated or -catalyzed fluoroalkylation has emerged as a highly efficient alternative pathway for the introduction of difluoroalkyl groups (CF2H) into alkenes.4 Recently, commercially available α,β-unsaturated carboxylic acids have been used as attractive reactants for metalcatalyzed decarboxylative Cvinyl−CF2H cross-coupling reactions.4f,i,5 For example, transition-metal-catalyzed difluoromethylation of α,β-unsaturated carboxylic acids utilizing Fe,5a Cu,4i,5a,6 and Ni7 as catalysts has been extensively reported (Scheme 1, eq 1). Furthermore, visible light photoredox catalysis has attracted substantial attention because the process serves as an environmentally friendly method for promoting selective radical reactions.8 More recently, Liu and co-workers9 reported a direct difluoroalkylation of α,β-unsaturated carbox© 2017 American Chemical Society
ylic acids with the dual-catalysis system merging photocatalysis and copper catalysis (Scheme 1, eq 2). Although those works represent very promising advances, metal-catalyzed protocols usually have several inherent limitations, including expensive metal catalysts and environmental toxicity. Meanwhile, pharmaceutical guidelines have enforced strict restrictions on the maximum amount of trace metal impurities allowed in pharmaceuticals. Therefore, it is still necessary to develop a metal-free method in fluorine chemistry, which is very significant for environmental and economic considerations. Herein, we disclose a general and efficient method for fluoroalkylation of cinnamic acids under metal-free conditions (Scheme 1, eq 3). The advantages of this reaction include the following: (a) Eosin Y, an organic dye, is less toxic and cheaper Received: July 12, 2017 Published: September 13, 2017 5501
DOI: 10.1021/acs.orglett.7b02129 Org. Lett. 2017, 19, 5501−5504
Letter
Organic Letters compared to transition-metal catalysts.10 (b) Both mono- and difluoromethyl-substituted alkenes can be synthesized by our system. (c) The process of decarboxylative fluoromethylation using the Eosin Y catalytic system could take place under mild conditions and without any metal. This reaction is practical and useful in the synthesis of alkene fluorides. In preliminary investigations, we used 4-methylcinamic acid (1a) and ethyl bromodifluoroacetate (2a) as the model substrates. 4-Methylcinamic acid (1a) and ethyl bromodifluoroacetate (2a) were reacted in the presence of Eosin Y (5 mol %), IBDA11 (or IB), and iPr2NEt (2 equiv) under visible light irradiation from a 15 W house bulb in DCE/H2O (1:1, 2 mL). Unfortunately, the desired product was not observed at all (Table 1, entries 1 and 2). Chen and co-workers12 reported
Subsequently, different solvents, light sources, and reactant concentrations were examined to improve the reaction efficiency. Experiments proved that a mixed solvent comprising DCE/H2O was more efficient than others such as MeCN/H2O, DMF/H2O, DMSO/H2O, etc. (Table 1, entries 7−9). When the model reaction was performed under green LED or blue LED irradiation, 52% and 48% yields of 3a were obtained, respectively (Table 1, entries 10 and 11). Meanwhile, decreasing the concentration of the reactants improved the reaction efficiency (Table 1, entry 12). Ultimately, the optimized conditions for the generation of 3a were determined as 2a (0.1 mmol) and 1a (2 equiv) in the presence of Eosin Y (5 mol %), BI-OH (2 equiv), and iPr2NEt (2 equiv) in DCE/ H2O (1:1, 2 mL) at room temperature for 12 h. Additional control experiments indicated that the photocatalyst, BI-OH, base, and light were all crucial for this reaction (Table 1, entries 15−18). Under the optimized reaction conditions (Table 1, entry 12), the scope of α,β-unsaturated carboxylic acids for this transformation was subsequently examined. As depicted in Scheme 2, the substrates bearing both electron-rich and electron-poor groups on the aromatic ring was well tolerated in this process (3a−e and 3g−q). It was noteworthy that the reactions between 3- or 4-chlorocinnamic acid or 4-bromocinnamic acid with 2a all proceeded to form the decarboxylative products with the halogen substituents untouched during the reactions, rendering the coupling products good candidates for further transformations such as transition-metal-catalyzed functionalization of carbonhalogen bond. In addition, meta- and orthosubstituted cinnamic acids also gave moderate yields of the products (3j−q), which indicated that the steric effect in the aromatic core was not pronounced. Moreover, di- and trisubstituted aromatic α,β-unsaturated carboxylic acids bearing electron-donating groups gave the desired products in moderate to good yields (3s, 3t, and 3w). Meanwhile, disubstituted cinnamic acids bearing electron-withdrawing groups were compatible in this transformation as well (3u). Cinnamic acids with a naphthyl group were also suitable under the standard conditions and the corresponding monofluoroacetylated products (3v) were obtained in reasonable yields. No products were obtained by coupling heteroarene substituted acrylic acids with ethyl bromodifluoroacetate under these conditions. Given the importance of the monofluoromethylene group, we examined ethyl bromofluoroacetate (or ethyl iodofluoroacetate) (2b) as a fluoroalkylating regent. Notably, the corresponding monofluorinated intermediates were observed under our optimal reaction conditions. Subsequently, the optimized reaction conditions were applied to a variety of cinnamic acids. As shown in Scheme 3, a series of electron-rich and electron-deficient cinnamic acids reacted well with monofluoroalkyl bromide, and the corresponding products (4a, 4b, and 4d−k) were obtained in moderate to good yields. Polyphenylcinnamic acid was also suitable under the optimized conditions, and the corresponding monofluoroacetylated product (4l) was obtained in reasonable yield. However, cinnamic acid derivatives with strong electron-withdrawing groups (CN, NO2, and OH) and heteroaryl boronic acids were not suitable coupling partners under these conditions. We next focused our attention on the synthetic application of alkene fluorides, and a satisfactory result (54% yield) was obtained when the reaction was performed on a gram scale (Scheme 4).
Table 1. Optimization of the Reaction Conditionsa,b
entry
HIR
PC
solvents
yieldb (%)
1 2 3 4 5 6 7 8 9 10c 11d 12e 13e 14e,f 15 16g 17h 18
IBDA IB BI-OAc BI-OH BI-OH BI-OH BI-OH BI-OH BI-OH BI-OH BI-OH BI-OH BI-OH BI-OH BI-OH BI-OH BI-OH
Eosin Y Eosin Y Eosin Y Eosin Y Ru(bpy)3Cl2 Rose Bengal Eosin Y EosinY Eosin Y Eosin Y Eosin Y Eosin Y Eosin Y Eosin Y
DCE/H2O DCE/H2O DCE/H2O DCE/H2O DCE/H2O DCE/H2O MeCN/H2O DMF/H2O DMSO/H2O DCE/H2O DCE/H2O DCE/H2O DCM/H2O DCE/H2O DCE/H2O DCE/H2O DCE/H2O DCE/H2O
0 0 48 61 0 30 20
