Bin He,
Zhiwei Xiao,
Hao Wu,
Yong Guo,
Qing-Yun Chen* and
Chao Liu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China. E-mail: chaoliu@sioc.ac.cn
First published on 3rd January 2017
A straightforward silver-mediated oxidative decarboxylative radical trifluoromethylthiolation reaction of aliphatic carboxylic acid is described. This reaction operates under mild conditions and allows the synthesis of various valuable alkyltrifluoromethylthioethers from abundant alkyl carboxylic acids and convenient nucleophilic AgSCF3 reagent. It provides a practical and efficient approach for the preparation of alkyltrifluoromethylthioethers.
Aliphatic carboxylic acids are cheap and abundant raw materials, and have been widely used as desirable starting materials for the preparation of many important and valuable compounds with different functional groups. The fundamental transformation process involves decarboxylation with the release of traceless by-product CO2 to generate alkyl radicals, and their subsequent reactions with a variety of reagents lead to efficient formation of many functionalized compounds. This important transformation process has been applied in several elegant decarboxylative fluorinations.8 Shen and co-workers described the silver-catalyzed oxidative decarboxylative trifluoromethylthiolation of alkyl carboxylic acids with electrophilic trifluoromethylthiolating reagent I in an aqueous emulsion (Scheme 1a).8b Very recently, Glorius group reported the visible-light-promoted decarboxylative trifluoromethylthiolation of alkyl carboxylic acids with electrophilic trifluoromethylthiolating reagent II under mild conditions (Scheme 1b).8f Although these methods are effective for the site-selective formation of C(sp3)–SCF3, they utilize relatively expensive electrophilic trifluoromethylthiolating reagents as the CF3S source, which are commonly prepared from readily available AgSCF3.
Recently, we developed a practical and efficient method for the direct trifluoromethylthiolation of unactivated C(sp3)–H bonds by AgSCF3/K2S2O8 under mild conditions.7b However, the regioselectivity of the reaction generally depends on the alkyl radical stability in situ formed, and several regioselective isomers are often generated in many cases. With the aim of overcoming the issue and further expanding the scope of the oxidative radical trifluoromethylthiolation methodologies, herein we report an efficient and general site-selective preparation of alkyltrifluoromethylthioethers by means of oxidative decarboxylative radical trifluoromethylthiolation of various aliphatic carboxylic acids by AgSCF3/selectfluor (Scheme 1c).
Entry | AgSCF3 (equiv.) | Oxidant (equiv.) | Solvent | Yieldb (%) |
---|---|---|---|---|
a Reaction conditions: decanoic acid (0.2 mmol, 1.0 equiv.), AgSCF3 (1.0–2.0 equiv.), oxidant (2.0–4.0 equiv.), and solvent (2.0 mL) at 60 °C for 4 hours under Ar atmosphere.b Yields were determined by 19F NMR spectroscopy with benzotrifluoride as the internal standard.c A di-trifluoromethylthiolation isomer mixture was obtained.d Acetone/CH3CN (1:1 v/v) was used.e Acetone/H2O (4:1 v/v) was used.f 2,6-Lutidine (2.0 equiv.) was used as ligand.g CuSCF3 was used instead of AgSCF3. | ||||
1 | 1.0 | K2S2O8 (2.0) | CH3CN | 0 |
2 | 1.0 | Na2S2O8 (2.0) | CH3CN | 37c |
3 | 1.0 | (NH4)2S2O8 | CH3CN | 28c |
4 | 1.0 | Selectfluor (2.0) | Acetone | 31 |
5 | 1.0 | Selectfluor (2.0) | CH3CN | 1 |
6 | 1.0 | Selectfluor (2.0) | DMF | 3 |
7 | 1.0 | Selectfluor (2.0) | Acetone/CH3CN | 3d |
8 | 1.0 | Selectfluor (2.0) | Acetone/H2O | 0e |
9 | 1.0 | NFSI (2.0) | Acetone | 25 |
10 | 1.0 | FP (2.0) | Acetone | 5 |
11 | 2.0 | Selectfluor (2.0) | Acetone | 54 |
12 | 2.0 | Selectfluor (4.0) | Acetone | 65 |
13 | 2.0 | Selectfluor (4.0) | Acetone | 82f |
14 | 2.0 | Selectfluor (4.0) | Acetone | 0g |
Next, we were delighted to find that when selectfluor was used as oxidant, the desired oxidative decarboxylative monotrifluoromethylthiolation product 2a was obtained and no undesired di-trifluoromethylthiolation products were observed, demonstrating the successful suppression of the undesired direct trifluoromethylthiolation of C(sp3)–H (Table 1, entry 4). Notably, neither competitive oxidative decarboxylative fluorination reaction was observed, which was considered to presumably occur under the reaction conditions according to literature.8a These results demonstrate that oxidative decarboxylative trifluoromethylthiolation under the reaction conditions is the predominant process presumably because selectfluor would not activate the C(sp3)–H to give the corresponding key C(sp3)-centered radical intermediate. Among several common reaction solvents we screened, acetone was the best one and provided 31% yield of the desired product 2a (Table 1, entries 4–7). It is worth noting that water was harmful for the reaction and resulted in no formation of the desired product (Table 1, entry 8). Then various oxidants such as N-fluorobenzenesulfonimide (NFSI), and 1-fluoropyridium tetrafluoroborate (PF) were further tested, it turned out that worse results were observed (Table 1, entries 9 and 10). By changing the amount of AgSCF3/selectfluor, the yield of the desired product 2a was further improved to 65% (Table 1, entries 11 and 12). The influence of several ligands were also estimated, 2,6-lutidine gave the best yield of 82% (Table 1, entry 13), which might coordinate with active Ag species to enhance their stability during the reaction.10 Furthermore, the replacement of AgSCF3 with CuSCF3 led to no formation of the desired product, demonstrating the key role of the free silver cation for the reaction (Table 1, entry 14). All these experimental results indicate that a combination of AgSCF3 (2.0 equiv.)/selectfluor (4.0 equiv.)/2,6-lutidine (2.0 equiv.) in acetone at 60 °C for 4 hours is established as the optimal conditions for oxidative decarboxylative trifluoromethylthiolation reactions of various aliphatic carboxylic acids.
With the optimal conditions in hand, we then explored the generality of the oxidative decarboxylative trifluoromethylthiolation reactions with a variety of aliphatic carboxylic acids (Scheme 3). It was found that various aliphatic carboxylic acids including primary, secondary and tertiary carboxylic acids are all suitable substrates for the oxidative decarboxylative trifluoromethylthiolation reactions. For example, a number of primary alkyl carboxylic acids underwent smooth oxidative decarboxylative trifluoromethylthiolation to give the desired alkylthifluormethylthioethers in isolated yields of 48–84% (2a–k). Secondary aliphatic carboxylic acids could also be subjected to the reactions to provide the corresponding products in modest to good yields (2l–q). When tertiary alkyl carboxylic acids were employed as the substrates, the desired oxidative decarboxylative trifluoromethylthiolation products were generated in acceptable yields (2r, s). It should be mentioned that reduced reaction time should be applied to the aliphatic carboxylic acids 1j and 1l since significant decrease in the yields of the corresponding desired trifluoromethylthiolation products was observed under the optimal reaction conditions,10 which might be due to the instability of the corresponding products 2j and 2l under the reaction conditions. With regard to the potential of the reaction in late-stage functionalization of valuable synthetic intermediates, a structurally complicated biologically active steroid derivative was applied to the oxidative decarboxylative trifluoromethylthiolation reaction and the desired product 2k was produced smoothly in good isolated yield. Its structure was unambiguously assigned by various spectral analysis, including X-ray single-crystal analysis.
To gain some understanding on the reaction pathway, a radical inhibitor (hydroquinone) or a radical scavenger (2,2,6,6-tetramethyl-1-piperidinyloxy, TEMPO) were added to the reaction of 1a, and a sharp decrease in the yield was observed for both cases.10 These preliminary results combined with previous reports on silver-mediated oxidative decarboxylative functionalization7,8a,b indicate that the reaction proceeds through a radical pathway.10 First, AgSCF3 is oxidized by selectfluor to generated Ag(II)SCF3 intermediate, CF3S radical or CF3SSCF3. Ag(II) combines with alkyl carboxylic acids to generate the corresponding alkyl radical via decarboxylation pathway. Then, the produced alkyl radical attacks a CF3S radical, CF3SSCF3, or abstracts the CF3S ligand of Ag(II)SCF3 intermediate to provide the desired oxidative decarboxylative trifluoromethylthiolation product (Scheme 4).
Footnote |
† Electronic supplementary information (ESI) available. CCDC 1484006. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra26133g |
This journal is © The Royal Society of Chemistry 2017 |