Selective hydrolysis of α -oxo ketene N , S -acetals in water: switchable aqueous synthesis of β -keto thioesters and β -keto amides

An eco-friendly selective hydrolysis of chain α -oxo ketene N , S -acetals in water for the switchable synthesis of β -keto thioesters and β -keto amides is reported. In refluxing water, the hydrolysis reactions of α -oxo ketene N , S -acetals in the presence of 1.0 equiv of dodecylbenzenesulfonic acid effectively afforded β -keto thioesters in excellent yield, while β -keto amides were successfully obtained in excellent yield when the hydrolysis reactions were carried out in the presence of 3.0 equiv of NaOH. The green approach to β -keto thioesters and β -keto amides avoids the use of harmful organic solvents, thiols and thiolacetates as well as amines, which could result in serious environmental and safety issues.


Results and Discussion
At the outset of our studies, to optimize the reaction conditions for the selective synthesis of β-keto thioesters and β-keto amides, we explored the hydrolysis reaction of (E)-3-(ethylthio)-1-phenyl-3-(phenylamino)prop-2-en-1-one (1a, 0.25 mmol, 70.8 mg) in water under different conditions (Table 1).We initially tested the reaction in the presence of dodecylbenzenesulfonic acid (DBSA) in boiling water and found that the amount of DBSA has a dramatic influence on this reaction.Using 1.0 equiv of DBSA, the reaction efficiently gave the desired S-ethyl 3-oxo-3-phenylpropanethioate (2a) in 91% yield (Table 1, entry 1).However, increasing the amount of DBSA to 2.0 equiv, the yield of 2a did not improve remarkably (Table 1, entry 2), and reducing the amount of DBSA resulted in a lower yield of 2a (Table 1, entry 3).Additionally, when DBSA was replaced by other acids such as H 2 SO 4 and CF 3 SO 3 H, the reaction showed poor effectiveness due to the poor solubility of 1a in water (Table 1, entries 4 and 5).Most notably, 2a was an inseparable mixture of keto and enol isomers, reaching a keto/enol ratio of 5:4 as determined by 1 H NMR spectroscopy.Thus, the optimized reaction conditions for the synthesis of 2a were determined to be 1.0 equiv of DBSA as catalyst and reflux temperature (conditions A).Subsequently, we turned our attention to the hydrolysis reaction in the presence of hydroxide for the preparation of 3-oxo-N,3diphenylpropanamide (3a).Firstly, we chose NaOH to optimize the reaction conditions.Apparently, in the absence of a solubilizer, no reaction occurred due to poor solubility of 1a in boiling water (Table 1, entry 6).Macrogol 400 (PEG-400) is emerging as an environmentally friendly nonionic solubilizer due to its unique merits, such as nontoxicity, inexpensiveness, nonflammability, low volatility and good water solubility, which are consistent with the concept of green chemistry [74,75].Therefore, we tested the reaction in the presence of PEG-400 (Table 1, entries 7-9).It was found that the reaction uniquely produced 3a in 48% yield when using 3.0 equiv of PEG-400 as solubilizer (Table 1, entry 8), and further increasing the PEG-400 loading could not remarkably improve the yield of 3a (Table 1, entry 9).With this in mind, we selected 3.0 equiv of PEG-400 as solubilizer in our study.Next, we examined the influence of the amount of NaOH on the reaction (Table 1, entries 10-12).The reaction obviously showed dependence on the amount of NaOH, and 3a was obtained in 90% yield when the reaction ran for 24 h in the presence of 3.0 equiv of NaOH (Table 1, entry 11).However, when lowering the reaction temperature to 90 °C, the reaction efficiency significantly decreased (Table 1, entry 13).Alike 2a, the keto isomer of 3a was the dominant isomer, with a keto/enol ratio of 3:1.
Then, we tested the effects of different bases on the reaction and found that the strong bases NaOH and KOH gave 3a in high yield (Table 1, entries 11 and 14), while the reaction afforded 3a in low yield in the presence of weak bases such as Na 2 CO 3 and Et 3 N (Table 1, entries 15 and 16).Accordingly, the optimal reaction conditions for the synthesis of 3a were 3.0 equiv of NaOH as catalyst and reflux temperature (conditions B).
With the optimal reaction conditions in hand, we next examined the scope of the two hydrolysis reactions (Scheme 2).Initially, the hydrolysis reaction for the synthesis of β-keto thioesters 2 was investigated under conditions A, and the results are shown in Scheme 2. (E)-3-(Ethylthio)-1-aryl-3-(phenylamino)prop-2-en-1-ones 1a-l were smoothly hydrolyzed to produce a series of S-ethyl 3-oxo-3-arylpropanethioates 2a-l in excellent yield, wherein the electronic effects of electron-donating and electron-withdrawing groups on the aromatic ring adjacent to the carbonyl group did not impact the formation of the products 2a-l.A variety of valuable functional groups on the benzene ring of 1b-j, such as methyl, methoxy, trifluoromethyl, and halogen atoms (F, Cl, Br, I), were well compatible with Next, the generality of the synthesis of β-keto amides 3 under conditions B was investigated (Scheme 3).3-Oxo-N-phenyl-3arylpropanamides 3a-l and 3-oxo-N-aryl-3-phenylpropanamides 3m-v could be produced in excellent yield from the hydrolysis of α-oxo ketene N,S-acetals under conditions B. The results showed that electron-donating as well as electron-withdrawing substituents on the two phenyl rings in compounds 1, Scheme 4: Gram-scale hydrolysis reactions of 1a.such as methyl, methoxy, halogen atoms (F, Cl, Br, I), CF 3 and SO 2 CH 3 , were well tolerated, and their electronic effects insignificantly impacted the formation of 3. Similarly, N-benzyl-3-oxo-3-phenylpropanamide (3w) could also be obtained in 80% yield when the hydrolysis reaction of (E)-3-(benzylamino)-3-(ethylthio)-1-phenylprop-2-en-1-one (1aa) was carried out under conditions B.
Furthermore, to explore the synthetic practicality of the two chemical processes, the synthesis of 2a and 3a on a gram scale was tested using the hydrolysis reaction of 1a under conditions A and B, respectively.When the hydrolysis reactions of 1a were performed on a 5 mmol scale, 0.915 g of 2a and 1.028 g of 3a were obtained in 88% and 86% yield, respectively (Scheme 4).
Next, the EcoScale value of the hydrolysis reactions of 1a under conditions A and B was calculated [76] to evaluate the green metrics of the two aqueous reactions (Table 2).It was found that the two procedures showed EcoScale values of 82.5 and 77.0, respectively, which indicated that the two procedures exhibited good environmental friendliness.
Based on the results above and on literature precedents [40,41], a plausible mechanistic pathway for the formation of 2 and 3 is shown in Scheme 5 (with the of 1a as an example).In

Conclusion
In summary, we have successfully developed an environmentally friendly method for the selective aqueous synthesis of β-keto thioesters and β-keto amides by simply changing reaction conditions.These features, including a good substrate scope, excellent yield and selectivity and ease of scale-up, rendered the green hydrolysis reaction very environment-friendly, practical, and attractive.
Experimental 1 H and 13 C{ 1 H} NMR spectra were recorded on a Bruker DRX-600 spectrometer and all chemical shift values are referenced to TMS (δ = 0.00 ppm for 1 H) and CDCl 3 (δ = 77.16ppm for 13 C).HRMS analysis was achieved with a Bruck microTof using the ESI method.All melting points are uncorrected.Analytical TLC plates (Sigma-Aldrich silica gel 60 F200) were analyzed under UV light (254 nm).Chromatographic purifications were performed on SDZF silica gel 160.
Typical procedure for the preparation of β-keto amides 3 (3a as an example) A mixture of (E)-3-(ethylthio)-1-phenyl-3-(phenylamino)prop-2-en-1-one (1a, 70.8 mg, 0.25 mmol), NaOH (30 mg, 0.75 mmol) and PEG-400 (0.236 mL, 0.75 mmol) in water (2 mL) was stirred at reflux in an oil bath under air for 24 h until 1a was completely consumed, as confirmed by TLC monitoring.Then, the pH value of the reaction mixture was adjusted to neutral using a 10% CH 3 COOH solution, and the reaction mixture was extracted with CH 2 Cl 2 (3 × 20 mL).The organic solution was dried with anhydrous Na 2 SO 4 , and the crude product was purified by column chromatography on 30-400 mesh

Table 1 :
Optimization of the reaction conditions.
b Isolated yield.c Recovery rate of 1a.d Reaction at 90 °C.