Guangwei Ronga,
Jincheng Mao*ab,
Defu Liua,
Hong Yana,
Yang Zhenga and
Jie Chena
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. China. E-mail: jcmao@suda.edu.cn
bState Key Laboratory of Oil and Gas Reservoir Geology and Exploitation, Southwest Petroleum University, Chengdu 610500, P. R. China
First published on 10th March 2015
Copper-catalyzed decarboxylative coupling between α-oxocarboxylic acids and diphenyl disulfides or thiophenols is presented, which provided an effective and direct approach for the preparation of useful thioesters through C(sp2)–S bond formation.
As we know that thioesters play pivotal roles in biology as they are important structure units in various natural compounds. Besides, they also serves as essential synthetic intermediates for a range of acyl transfer reactions.6 Traditionally, thioester was prepared from benzoyl chloride and thiophenol. Considering the hygroscopicity and instability of benzoyl chloride, more practical approaches were developed using benzaldehydes as starting materials in recent years.7 Unlike previous reported protocols, thioesterification also can also be achieved through α-oxocarboxylic acids and disulfides with our method, which provides an alternative way to access thioesters.
In our initial attempt, benzoylformic acid and diphenyl disulfide were chosen as model substrates to screen the optimal reaction conditions and the results are shown in Table 1. Using 20 mol% of cupric acetate as catalyst, stoichiometric (NH4)2S2O8 as oxidant and acetonitrile as solvent, desired product was achieved in the yield of 28% (Table 1, entry 1). Controlled experiments confirmed that the reaction can not occur without catalyst or oxidant. The reaction also can not proceed smoothly using the traditional system of Ag(I)/(NH4)2S2O8. Then, we screened various copper catalysts and CuO showed best catalytic efficiency, affording the product 3a in 33% yield (Table 1, entry 7). Different oxidant were tested and (NH4)2S2O8 was proved to be one of the best (Table 1, entires 12–14). Most solvents were not suitable to this reaction during the process of optimization, only DMSO showed good effect and 65% 3a was achieved (Table 1, entry 12). Given that mixed solvent was widely adopted in decarboxylative reactions, we next tried various co-solvent such as DMSO/CH3CN and DMSO/dioxane in a ratio of 10:
1. We were pleased to find that 3a was obtained in 74% yield when DMSO/H2O as solvent (Table 1, entry 15). Through the adjustment of the proportion of solvent, we found that the optimum solvent ratio of DMSO/H2O was 5
:
1 and the yield was increased to 83% (Table 1, entry 18). The amount of 2a was also tested (Table 1, entries 19 and 20) and 2 equivalents proved to be the best. S-Phenyl benzenesulfonothioate was detected after the reaction which can explain why disulfide should be excessive.
Entry | Cat. | Oxidant | Solvent | Yieldb (%) |
---|---|---|---|---|
a Catalytic conditions: benzoylformic acid (0.3 mmol), diphenyl disulfide (0.3 mmol), cat. (20 mol%), oxidant (0.6 mmol), solvent (2 mL), 80 °C, 12 h, air.b Isolated yield.c 2a (0.15 mmol).d 2a (045 mmol). | ||||
1 | Cu(OAc)2 | (NH4)2S2O8 | CH3CN | 28 |
2 | Cu | (NH4)2S2O8 | CH3CN | 29 |
3 | CuI | (NH4)2S2O8 | CH3CN | Trace |
4 | CuCl2 | (NH4)2S2O8 | CH3CN | <10 |
5 | CuSO4 | (NH4)2S2O8 | CH3CN | 31 |
6 | CuF2 | (NH4)2S2O8 | CH3CN | 31 |
7 | CuO | (NH4)2S2O8 | CH3CN | 33 |
8 | CuO | (NH4)2S2O8 | Dioxane | NR |
9 | CuO | (NH4)2S2O8 | Toluene | NR |
10 | CuO | (NH4)2S2O8 | DCE | NR |
11 | CuO | (NH4)2S2O8 | DMF | NR |
12 | CuO | (NH4)2S2O8 | DMSO | 65 |
13 | CuO | K2S2O8 | DMSO | 50 |
14 | CuO | Na2S2O8 | DMSO | 45 |
15 | CuO | (NH4)2S2O8 | DMSO/H2O = 20/1 | 74 |
16 | CuO | (NH4)2S2O8 | DMSO/H2O = 10/1 | 78 |
17 | CuO | (NH4)2S2O8 | DMSO/H2O = 7/1 | 82 |
18 | CuO | (NH4)2S2O8 | DMSO/H2O = 5/1 | 83 |
19c | CuO | (NH4)2S2O8 | DMSO/H2O = 5/1 | 72 |
20d | CuO | (NH4)2S2O8 | DMSO/H2O = 5/1 | 83 |
With optimized reaction conditions in hand, we next investigated the scope of different α-oxocarboxylic acids. As shown in Table 2, various substituted α-oxocarboxylic acids, including methyl, halogen and methoxy groups, were tolerable under the optimal conditions. Generally, α-oxocarboxylic acids bearing an electron-donating group gave the products in higher yields than those with electron-withdrawing analogues. Methyl-substituted from 3b to 3d all proceeded well and gave in good yields (Table 2, entries 2–4). The yields of p-halogen substrates were decreased from 3e to 3g (Table 2, entries 5–7). It is the same situation for o-halogen substrates 3k and 3l (Table 2, entries 11 and 12). Meta-bromine benzoylformic acid afforded product (Table 2, entry 8) in lower yield than ortho and para-bromine acids. We guess that the poor conjugated effect perhaps caused the difference when bromine located in the meta position. For heterocyclic and fused ring substrates, 3m and 3n can be achieved in good yields of 79% and 82%, respectively. Furthermore, aliphatic α-oxocarboxylic acid was also suitable substrate in this reaction, giving a moderate yield (3o) (Table 2, entry 15).
Entry | R | Product | Yieldb [%] |
---|---|---|---|
a Catalytic conditions: benzoylformic acid (0.3 mmol), diphenyl disulfide (0.3 mmol), (NH4)2S2O8 (0.6 mmol), CuO (20 mol%), (NH4)2S2O8 (0.6 mmol), DMSO/water (5/1) (2 mL), 80 °C, 12 h, air.b Isolated yield. | |||
1 | C6H5 | 3a | 83 |
2 | 4-MeC6H4 | 3b | 84 |
3 | 3-MeC6H4 | 3c | 86 |
4 | 2-MeC6H4 | 3d | 82 |
5 | 4-FC6H4 | 3e | 81 |
6 | 4-ClC6H4 | 3f | 60 |
7 | 4-BrC6H4 | 3g | 51 |
8 | 3-BrC6H4 | 3h | 34 |
9 | 2-BrC6H4 | 3i | 54 |
10 | 4-MeOC6H4 | 3j | 86 |
11 | 2-FC6H4 | 3k | 60 |
12 | 2-ClC6H4 | 3l | 53 |
13 | 2-Thienyl | 3m | 79 |
14 | 2-Naphtyl | 3n | 82 |
15 | Methyl | 3o | 56 |
As shown in Table 3, we then applied the optimal reaction conditions to decarboxylations of benzoylformic acid with various disulfides. Aromatic disulfides can afford the desired esters in good yields. Disulfide bearing strong electron donating group such as methoxy was converted into the corresponding thioester 3q in 86% yield (Table 3, entry 2). However, the reaction was almost inhibited when p-nitro substituted disulfide was chosen as the substrate (Table 3, entry 3). It is pleased to find that aliphatic disulfides are good substrates, giving moderate yields (3r and 3s) (Table 3, entries 4 and 5).
As we know that thiols have disadvantages of operating inconvenience and unpleasant odour in comparison to disulfides. Considering the similarity of their structure, we further extended the reaction to a series of thiols. Various substituted thiols all gave the corresponding products in moderate to good yields as shown in Table 4. It is obvious to find that the desired thiols show less efficiency in thioesterification compared to disulfides. Anyway, it provides alternative choice of substrates as thiols are more cheaper and commercially available. It was found that disulfide was detected after reaction, which indicated that the reaction may go through a process that thiophenol was converted into the corresponding disulfide before reacting with benzoylformic acid.
Entry | R | Product | Yieldb [%] |
---|---|---|---|
a Catalytic conditions: benzoylformic acid (0.3 mmol), thiophenol (0.6 mmol), CuO (20 mol%), (NH4)2S2O8 (0.6 mmol), DMSO/water (5/1) (2 mL), 80 °C, 12 h, air.b Isolated yield. | |||
1 | C6H5 | 3a | 74 |
2 | 2-MeC6H4 | 3t | 73 |
3 | 2,6-Me2C6H3 | 3u | 75 |
4 | 2-ClC6H4 | 3v | 66 |
5 | 2-FC6H4 | 3w | 72 |
6 | 2-Thienyl | 3x | 45 |
Based on previous reports about decarboxylations,5a,7 we proposed a possible mechanism as shown in Scheme 2. Firstly benzoylformic acid generates benzoyl radical in the presence of copper(II) catalyst. The radical then further reacts with disulfide or thiophenol to give the thioester. The copper(I) ion will be next oxidized to copper(II) by ammonium persulfate and back into the reaction.
In conclusion, we have presented an efficient method to prepare thioesters involving C(sp2)–S bonds formation through decarboxylative coupling of α-oxocarboxylic acids and disulfides or thiophenols. Furthermore, the thioesters prepared by our method will show valuable properties such as nucleophile acceptors, which means they can serve as one of the most important intermediates in organic synthesis.8 Further application of the reaction will be the key point of our future work.
Footnote |
† Electronic supplementary information (ESI) available: Experimental procedures, 1H, 13C, spectral data and analytical data for the products. See DOI: 10.1039/c4ra15751f |
This journal is © The Royal Society of Chemistry 2015 |