Atom-Economic Synthesis of 4-Pyrones from Diynones and Water

Transition-metal-free synthesis of 4-pyrones via TfOH-promoted nucleophilic addition/cyclization of diynones and water has been developed. This transformation is simple, atom economical and environmentally benign, providing rapid and efficient access to substituted 4-pyrones.


Results and Discussion
1,5-Diphenylpenta-1,4-diyn-3-one (1a) was chosen as model substrate to identify the optimal conditions for this reaction (Table 1). Originally, the reaction was carried out in the presence of 1 equiv. TfOH for 24 h to afford the desired product 2a in 70% yield ( Under the optimized reaction conditions, the one-pot reaction worked well using all kinds of diynones, as shown in Scheme 1. Firstly, various symmetric diynones were identified as suitable substrates for the reaction and provided the desired products in moderate to good yields (Scheme 1, 2b−2j). Aryl groups with electron-donating groups (EDG) gave satisfactory yields (Scheme 1, 2b−2d and 2f−2h), whereas aryl groups with electron-withdrawing groups (EWG) afforded slightly lower yields (Scheme 1, 2e). Gratifyingly, aliphatic diynones worked smoothly to generate the

Results and Discussion
1,5-Diphenylpenta-1,4-diyn-3-one (1a) was chosen as model substrate to identify the optimal conditions for this reaction (Table 1). Originally, the reaction was carried out in the presence of 1 equiv. TfOH for 24 h to afford the desired product 2a in 70% yield (

Results and Discussion
1,5-Diphenylpenta-1,4-diyn-3-one (1a) was chosen as model substrate to identify the optimal conditions for this reaction (Table 1). Originally, the reaction was carried out in the presence of 1 equiv. TfOH for 24 h to afford the desired product 2a in 70% yield ( Under the optimized reaction conditions, the one-pot reaction worked well using all kinds of diynones, as shown in Scheme 1. Firstly, various symmetric diynones were identified as suitable substrates for the reaction and provided the desired products in moderate to good yields (Scheme 1, 2b−2j). Aryl groups with electron-donating groups (EDG) gave satisfactory yields (Scheme 1, 2b−2d and 2f−2h), whereas aryl groups with electron-withdrawing groups (EWG) afforded slightly lower yields (Scheme 1, 2e). Gratifyingly, aliphatic diynones worked smoothly to generate the Under the optimized reaction conditions, the one-pot reaction worked well using all kinds of diynones, as shown in Scheme 1. Firstly, various symmetric diynones were identified as suitable substrates for the reaction and provided the desired products in moderate to good yields (Scheme 1, 2b-2j). Aryl groups with electron-donating groups (EDG) gave satisfactory yields (Scheme 1, 2b-2d and 2f-2h), whereas aryl groups with electron-withdrawing groups (EWG) afforded slightly lower yields (Scheme 1, 2e). Gratifyingly, aliphatic diynones worked smoothly to generate the corresponding cyclization products 2i and 2j in 50% and 57%, respectively (Scheme 1, 2i and 2j). After exploring the reaction substrate scope of symmetric diynones, we next examined asymmetric diynones substrates. To our delight, the corresponding 4-pyrones products were obtained in moderate to good yields under the standard conditions (Scheme 1, 2k-2r). The desired products 2k-2q were obtained in 55%-78% yields when asymmetric diynones substrates 1k-1q (R 2 = Ph, R 1 = aryl-or alkyl-) were subjected to this reaction. Obviously, aryl groups with electron-donating groups gave higher yields than diynones featuring electron-withdrawing groups on the phenyl ring (Scheme 1, 2l and 2m vs. 2n and 2p). Notably, diynone 1p, which possess an electron-withdrawing group at the ortho-position of the phenyl ring (R 1 = 2-Cl-Ph, R 2 = Ph) reacted readily to afford 2p in 61% yield (Scheme 1, 2p). Furthermore, diynone 1q, which bear both a EDG-incorporated aryl ring and a EWG-incorporated aryl ring (R 1 = 4-OMe-Ph, R 2 = 4-F-Ph) also participated well in the reaction and offered 2q in 63% yield (Scheme 1, 2q). Finally, diynone 1r also worked smoothly to give 2r in 50% yield (Scheme 1, 2r). corresponding cyclization products 2i and 2j in 50% and 57%, respectively (Scheme 1, 2i and 2j).
TfOH (1 equiv.) To better understand the reaction mechanism, we carried out control experiments as outlined in Scheme 2. Deuterium-labeled D2O was used in the reaction with diynone 1a to give the deuterium-labeled product 2a-d in 80% yield, where over 95% of deuterium was incorporated into the cyclization product.
This result demonstrated that H2O was introduced into the 4-pyrones. Moreover, an O 18 -labeled experiment further showed that H2O reacted with diynones to form 4-pyrones.
On the basis of the above results and existing literature [78], a plausible mechanistic description of the nucleophilic addition and cyclization reaction is shown in Scheme 3. First, the carbonyl of the diynone substrate was activated by TfOH, followed by nucleophilic addition of H2O to the carbon−carbon triple bond of diynone and keto-enol tautomerization [79,80] to form intermediate A.
Then intermediate A was converted to B through protonation and C-C bond rotation, which was promoted by elevated temperature. Subsequently, an intramolecular nucleophilic attack of the oxhydryl group to the carbon−carbon triple bond of B lead to a cyclization intermediate C. Finally, deprotonation of C gave the desired 4-pyrone 2. To better understand the reaction mechanism, we carried out control experiments as outlined in Scheme 2. Deuterium-labeled D 2 O was used in the reaction with diynone 1a to give the deuterium-labeled product 2a-d in 80% yield, where over 95% of deuterium was incorporated into the cyclization product.
This result demonstrated that H 2 O was introduced into the 4-pyrones. Moreover, an O 18 -labeled experiment further showed that H 2 O reacted with diynones to form 4-pyrones.
On the basis of the above results and existing literature [78], a plausible mechanistic description of the nucleophilic addition and cyclization reaction is shown in Scheme 3. First, the carbonyl of the diynone substrate was activated by TfOH, followed by nucleophilic addition of H 2 O to the carbon−carbon triple bond of diynone and keto-enol tautomerization [79,80] to form intermediate A.
Then intermediate A was converted to B through protonation and C-C bond rotation, which was promoted by elevated temperature. Subsequently, an intramolecular nucleophilic attack of the oxhydryl group to the carbon−carbon triple bond of B lead to a cyclization intermediate C. Finally, deprotonation of C gave the desired 4-pyrone 2.
an Avance 500 spectrometer ( 1 H at 500 MHz and 13 C at 125 MHz) or an Avance 400 spectrometer ( 1 H at 400 MHz and 13 C at 100 MHz) (Bruker Corporation, Karlsruhe, Germany). IR spectra were recorded on a Nicolet ESP 360 FT-IR spectrometer (Nicolet, Madison, WI, USA) and only major peaks are reported in cm −1 . High resolution mass spectra (HRMS) were recorded on an Exactive Mass Spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) equipped with ESI or APCI ionization sources. Unless stated otherwise, commercial reagents were used without further purification. All reagents were weighed and handled at room temperature. Compounds 1a-1r were prepared by the reported methods [78,81]. The NMR spectra and HRMS spectra of the products can be found in the Supplementary Materials.

General Procedure for the Synthesis of Compound 2
The reaction mixture of 1 (0.5 mmol), TfOH (1 equiv.) and H 2 O (1 mL) in a 15 mL test tube was stirred at 100 • C for 36 h, and monitored periodically by TLC. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with water and brine, dried over MgSO 4 and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography (petroleum ether and ethyl acetate, v/v = 5:1 to 2:1) to afford 4-pyrones 2 (Scheme 5). sources. Unless stated otherwise, commercial reagents were used without further purification. All reagents were weighed and handled at room temperature. Compounds 1a-1r were prepared by the reported methods [78,81]. The NMR spectra and HRMS spectra of the products can be found in the Supplementary Materials.

Deuterium Labeling Experiments
The reaction mixture of 1 (0.5 mmol), TfOH (1 equiv.), and D2O (1 mL) in a 15 mL test tube was stirred at 100 °C for 36 h, and monitored periodically by TLC. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with water and brine, dried over MgSO4 and filtered. The solvent was removed under vacuum.

O 18 -Labelling Experiment
The reaction mixture of 1a (0.5 mmol), TfOH (1 equiv.), and H2O 18 (1 mL) in a 15 mL test tube was stirred at 100 °C for 36 h, and monitored periodically by TLC. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with water and brine, dried over MgSO4 and filtered. The solvent was Scheme 6. Deuterium Labeling Experiments.

O 18 -Labelling Experiment
The reaction mixture of 1a (0.5 mmol), TfOH (1 equiv.), and H 2 O 18 (1 mL) in a 15 mL test tube was stirred at 100 • C for 36 h, and monitored periodically by TLC. Upon completion, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with water and brine, dried over MgSO 4 and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography (petroleum ether and ethyl acetate, v/v = 5:1 to 2:1) to afford 4-pyrone O 18 -2a (78%) (Scheme 7).

Gram-Scale Synthesis
The reaction mixture of 1a (5 mmol), TfOH (1 equiv.) and H2O (10 mL) in a 50 mL round-bottom flask was stirred at 100 °C for 36 h, and monitored periodically by TLC. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water and brine, dried over MgSO4 and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography (petroleum ether and ethyl acetate, v/v = 5:1 to 2:1) to afford 4-pyrone 2a (53%) (Scheme 8).

Conclusions
We have developed a simple and efficient transition-metal-free method for the synthesis of substituted 4-pyrones from diynones and H2O. Water is a cheap, green and readily available staring material, which converted to the desired 4-pyrone products via a nucleophilic addition/cyclization/ dehydrogenation process. The operational simplicity, good yields, and environmentally benign nature of this method make it an attractive route to 4-pyrones. Further studies on the applications of 4-pyrones in drug design are currently ongoing in our laboratory.
Author Contributions: Yan-Li Xu and Qing-Hu Teng conceived and designed the experiments. The experimental work was conducted by Qing-Hu Teng under the supervision of Ying-Ming Pan and Xian-Li Ma who are the lead author; Qing-Hu Teng and Wei Tong analyzed the data; Heng-Shan Wang contributed reagents/materials/analysis tools; Yan-Li Xu and Qing-Hu Teng wrote the paper.

Conflicts of Interest:
The authors declare no conflict of interest.