Montmorillonite K10-Catalyzed Solvent-Free Conversion of Furfural into Cyclopentenones

A simple and eco-friendly montmorillonite K10 (MK10)-catalyzed method for the synthesis of cyclopentenone derivatives from biomass-produced furfural has been developed. The versatility of this protocol is that the reactions were performed under solvent-free conditions and in a short reaction time under heterogeneous catalysis. Montmorillonite K10 is mostly explored as a heterogeneous catalyst since it is inexpensive and environmentally friendly.


Introduction
In the last few decades, the use of heterogeneous catalysis has become a promising field in chemical synthesis, especially in industrial applications [1]. From an economic point of view, the tendency to use heterogeneous acid catalysis in the industrial field derives from their intrinsic stability, ease of recovery, separation and recycling minimizing waste contamination. On the other hand, the use of volatile and dangerous solvents in the chemical industry represents a risk for the environment and human health [2][3][4][5][6], so that the necessity for clean processes, in which energy, waste and costs are reduced, is of general concern [7].
The Pollution Prevention Act of 1990 was endorsed to raise interest in pollution prevention, and to encourage the design of environmentally benign processes and products.
Lowering the environmental impact of industrial activities is particularly important for the pharmaceutical industry, as it is very often indicated as the principal source of environmental pollution [45]. In recent years, the use of renewable sources or waste materials as starting products has become

Results
In our initial experiment, we choose morpholine as an amine substrate to be added to 2-furaldehyde to selectively obtain trans-4,5-dimorpholinocyclopent-2-enone. The studies conducted for the development and optimization of the cyclization rearrangement of furfural and morpholine are presented in Table 1.
Although the complete conversion of furfural at room temperature was observed, the confirmation that the procedure could work better was recorded when the same reaction was conducted at higher temperatures, observing a total conversion with better selectivity in only 35 minutes (Table 1, entries 2 and 3).  We observed a better conversion with higher selectivity toward the desired product when the amount of catalyst was increased at 20 wt % when performing the reaction at 80 °C (Table 1, Entry 4); comparable selectivity was achieved by increasing the temperature (Table 1, Entry 5). Under the same reaction conditions, but in the absence of a catalyst, no complete conversion of furfural, and poor selectivity were observed (Table 1, entry 6). Based on our skills in the development of ecofriendly and selective procedures [54,55], we tested the microwave activation of the reaction, finding that the microwave irradiation at 60 °C gave the best results in terms of reaction rate and product yield (Table 1, entries 7-9). Surprisingly, we obtained the desired product at 99% yield in only 5 min at 60 ° C ( Table 1, entry 8).
Furthermore, we have evaluated the recyclability of the heterogeneous catalyst in the model reaction. The final reaction mixture, including MK10 and the product, was treated with a green solvent such as ethyl acetate [81]; the catalyst was separated from the solution by filtration, washed with ethyl acetate (3 mL) four times, and dried in an oven (80 °C) to remove traces of the solvent. Afterwards, the combined organic phases were concentrated under a vacuum, and the crude product was analyzed by GC-MS. The recovered catalyst was used directly for the next run, with the addition of fresh reagents. Thus, the second reaction mixture was subjected again to the above-described procedure, and further reaction cycles were repeated by using the previously recycled MK10.
To demonstrate the efficiency of the catalyst recycled: the MK10 can be recovered and recycled for three sequential cycles in the synthesis of trans-4,5-dimorpholinocyclopent-2-enone, furnishing high yields in every single cycle ( Figure 1). The recycling showed the real heterogeneous catalytic nature for the rearrangement reaction, and the stable structure of MK10. We observed a better conversion with higher selectivity toward the desired product when the amount of catalyst was increased at 20 wt % when performing the reaction at 80 • C (Table 1, Entry 4); comparable selectivity was achieved by increasing the temperature (Table 1, Entry 5). Under the same reaction conditions, but in the absence of a catalyst, no complete conversion of furfural, and poor selectivity were observed (Table 1, entry 6). Based on our skills in the development of eco-friendly and selective procedures [54,55], we tested the microwave activation of the reaction, finding that the microwave irradiation at 60 • C gave the best results in terms of reaction rate and product yield (Table 1, entries [7][8][9]. Surprisingly, we obtained the desired product at 99% yield in only 5 min at 60 • C ( Table 1, entry 8).
Furthermore, we have evaluated the recyclability of the heterogeneous catalyst in the model reaction. The final reaction mixture, including MK10 and the product, was treated with a green solvent such as ethyl acetate [81]; the catalyst was separated from the solution by filtration, washed with ethyl acetate (3 mL) four times, and dried in an oven (80 • C) to remove traces of the solvent. Afterwards, the combined organic phases were concentrated under a vacuum, and the crude product was analyzed by GC-MS. The recovered catalyst was used directly for the next run, with the addition of fresh reagents. Thus, the second reaction mixture was subjected again to the above-described procedure, and further reaction cycles were repeated by using the previously recycled MK10.
To demonstrate the efficiency of the catalyst recycled: the MK10 can be recovered and recycled for three sequential cycles in the synthesis of trans-4,5-dimorpholinocyclopent-2-enone, furnishing high yields in every single cycle ( Figure 1). The recycling showed the real heterogeneous catalytic nature for the rearrangement reaction, and the stable structure of MK10. Then, to prove the applicability of this eco-friendly process, the model reaction was performed on a scale of 10 mmol of furfural and 20 mmol of morpholine, using the respective amount of MK10. The reaction was accomplished in 10 min with 98% isolated yield after simple extraction with ethyl acetate.
At this point, the experimental procedure was applied to different amines to obtain the desired 4,5-diaminocyclopenten-2-enones, and quantitative yields superior to 90% were obtained in all cases ( Table 2). The reaction gave excellent results after the above reported simple workup with the alicyclic ( Table 2, Entries 2-4), aliphatic ( Table 2, Entries 5-7), and with the aromatic secondary amines ( Table  2, entries 8-9); this reaction takes place especially with secondary amines, by the formation of an enamine intermediate as proposed by a previously reported mechanism of reaction [60,61]. In the case of primary aliphatic amines, the corresponding imine was observed as the only product (Scheme 1).  Then, to prove the applicability of this eco-friendly process, the model reaction was performed on a scale of 10 mmol of furfural and 20 mmol of morpholine, using the respective amount of MK10. The reaction was accomplished in 10 min with 98% isolated yield after simple extraction with ethyl acetate.
At this point, the experimental procedure was applied to different amines to obtain the desired 4,5-diaminocyclopenten-2-enones, and quantitative yields superior to 90% were obtained in all cases ( Table 2). The reaction gave excellent results after the above reported simple workup with the alicyclic ( Table 2, Entries 2-4), aliphatic ( Table 2, Entries 5-7), and with the aromatic secondary amines ( Table 2, entries 8-9); this reaction takes place especially with secondary amines, by the formation of an enamine intermediate as proposed by a previously reported mechanism of reaction [60,61]. In the case of primary aliphatic amines, the corresponding imine was observed as the only product (Scheme 1). Then, to prove the applicability of this eco-friendly process, the model reaction was performed on a scale of 10 mmol of furfural and 20 mmol of morpholine, using the respective amount of MK10. The reaction was accomplished in 10 min with 98% isolated yield after simple extraction with ethyl acetate.
At this point, the experimental procedure was applied to different amines to obtain the desired 4,5-diaminocyclopenten-2-enones, and quantitative yields superior to 90% were obtained in all cases ( Table 2). The reaction gave excellent results after the above reported simple workup with the alicyclic ( Table 2, Entries 2-4), aliphatic ( Table 2, Entries 5-7), and with the aromatic secondary amines ( Table  2, entries 8-9); this reaction takes place especially with secondary amines, by the formation of an enamine intermediate as proposed by a previously reported mechanism of reaction [60,61]. In the case of primary aliphatic amines, the corresponding imine was observed as the only product (Scheme 1).                2,4-Diamino cyclopent-2-enone, a by-product observed in the cyclization, was obtained at room temperature or in the absence of a catalyst ( Table 1, entries 1 and 6) after a long reaction time. As previously observed [57,60], the conversion of 4,5-diamino cyclopentenone to 2,4-diamino cyclopentenone was performed in the presence of an excess of amine. To investigate the catalytic activity of MK10 and its selectivity, we tested the performance of trans-4,5-dimorpholinocyclopent-2-enone in the presence of a small amount of morpholine, to obtain 2,4-dimorpholinocyclopent-2enone (Scheme 2). Adding the amine (0.2 mmol) to the reaction mixture at room temperature without microwave irradiation, we observed that the 4,5-dimorpholino cyclopentenone was converted into the respective 2,4-cyclopentenone derivative after only one hour. In fact, the presence of excess amines leads to the formation of an enolic intermediate that successively yields the respective 2,4-cyclopentenone derivative. The mechanism of this reaction was proposed by Lewis and Mulquiney [82].
All reactions were monitored by GC-MS. The GC-MS Shimadzu workstation was constituted by a GC 2010 equipped with a QUADREX 007-5MS (30 m × 0.25 mm, 0.25 µm) capillary column, operating in "split" mode with 1 mL·min −1 flow of He as the carrier gas. 1 H-NMR spectra were recorded on a Brüker spectrometer at 300 MHz. Chemical shifts are reported in δ units (ppm), with tretramethylsilane (TMS) as the reference (δ 0.00). All coupling constants (J) are reported in hertz. Multiplicity is indicated by one or more of the following: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). 13 C-NMR spectra were recorded on a Brüker spectrometer at 75 MHz. Chemical shifts are reported in δ units (ppm) relative to CDCl3 (δ 77.0). 2,4-Diamino cyclopent-2-enone, a by-product observed in the cyclization, was obtained at room temperature or in the absence of a catalyst ( Table 1, entries 1 and 6) after a long reaction time. As previously observed [57,60], the conversion of 4,5-diamino cyclopentenone to 2,4-diamino cyclopentenone was performed in the presence of an excess of amine. To investigate the catalytic activity of MK10 and its selectivity, we tested the performance of trans-4,5-dimorpholinocyclopent-2-enone in the presence of a small amount of morpholine, to obtain 2,4-dimorpholinocyclopent-2enone (Scheme 2). Adding the amine (0.2 mmol) to the reaction mixture at room temperature without microwave irradiation, we observed that the 4,5-dimorpholino cyclopentenone was converted into the respective 2,4-cyclopentenone derivative after only one hour. In fact, the presence of excess amines leads to the formation of an enolic intermediate that successively yields the respective 2,4-cyclopentenone derivative. The mechanism of this reaction was proposed by Lewis and Mulquiney [82].
All reactions were monitored by GC-MS. The GC-MS Shimadzu workstation was constituted by a GC 2010 equipped with a QUADREX 007-5MS (30 m × 0.25 mm, 0.25 µm) capillary column, operating in "split" mode with 1 mL·min −1 flow of He as the carrier gas. 1 H-NMR spectra were recorded on a Brüker spectrometer at 300 MHz. Chemical shifts are reported in δ units (ppm), with tretramethylsilane (TMS) as the reference (δ 0.00). All coupling constants (J) are reported in hertz. Multiplicity is indicated by one or more of the following: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). 13  2,4-Diamino cyclopent-2-enone, a by-product observed in the cyclization, was obtained at room temperature or in the absence of a catalyst ( Table 1, entries 1 and 6) after a long reaction time. As previously observed [57,60], the conversion of 4,5-diamino cyclopentenone to 2,4-diamino cyclopentenone was performed in the presence of an excess of amine. To investigate the catalytic activity of MK10 and its selectivity, we tested the performance of trans-4,5-dimorpholinocyclopent-2-enone in the presence of a small amount of morpholine, to obtain 2,4-dimorpholinocyclopent-2enone (Scheme 2). Adding the amine (0.2 mmol) to the reaction mixture at room temperature without microwave irradiation, we observed that the 4,5-dimorpholino cyclopentenone was converted into the respective 2,4-cyclopentenone derivative after only one hour. In fact, the presence of excess amines leads to the formation of an enolic intermediate that successively yields the respective 2,4-cyclopentenone derivative. The mechanism of this reaction was proposed by Lewis and Mulquiney [82].
All reactions were monitored by GC-MS. The GC-MS Shimadzu workstation was constituted by a GC 2010 equipped with a QUADREX 007-5MS (30 m × 0.25 mm, 0.25 µm) capillary column, operating in "split" mode with 1 mL·min −1 flow of He as the carrier gas. 1 H-NMR spectra were recorded on a Brüker spectrometer at 300 MHz. Chemical shifts are reported in δ units (ppm), with tretramethylsilane (TMS) as the reference (δ 0.00). All coupling constants (J) are reported in hertz. Multiplicity is indicated by one or more of the following: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). 13 C-NMR spectra were recorded on a Brüker spectrometer at 75 MHz. Chemical shifts are reported in δ units (ppm) relative to CDCl3 (δ 77.0). 2,4-Diamino cyclopent-2-enone, a by-product observed in the cyclization, was obtained at room temperature or in the absence of a catalyst ( Table 1, entries 1 and 6) after a long reaction time. As previously observed [57,60], the conversion of 4,5-diamino cyclopentenone to 2,4-diamino cyclopentenone was performed in the presence of an excess of amine. To investigate the catalytic activity of MK10 and its selectivity, we tested the performance of trans-4,5-dimorpholinocyclopent-2-enone in the presence of a small amount of morpholine, to obtain 2,4-dimorpholinocyclopent-2enone (Scheme 2). Adding the amine (0.2 mmol) to the reaction mixture at room temperature without microwave irradiation, we observed that the 4,5-dimorpholino cyclopentenone was converted into the respective 2,4-cyclopentenone derivative after only one hour. In fact, the presence of excess amines leads to the formation of an enolic intermediate that successively yields the respective 2,4-cyclopentenone derivative. The mechanism of this reaction was proposed by Lewis and Mulquiney [82].
All reactions were monitored by GC-MS. The GC-MS Shimadzu workstation was constituted by a GC 2010 equipped with a QUADREX 007-5MS (30 m × 0.25 mm, 0.25 µm) capillary column, operating in "split" mode with 1 mL·min −1 flow of He as the carrier gas. 1 H-NMR spectra were recorded on a Brüker spectrometer at 300 MHz. Chemical shifts are reported in δ units (ppm), with tretramethylsilane (TMS) as the reference (δ 0.00). All coupling constants (J) are reported in hertz. Multiplicity is indicated by one or more of the following: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). 13 C-NMR spectra were recorded on a Brüker spectrometer at 75 MHz. Chemical shifts are reported in δ units (ppm) relative to CDCl3 (δ 77.0). 2,4-Diamino cyclopent-2-enone, a by-product observed in the cyclization, was obtained at room temperature or in the absence of a catalyst ( Table 1, entries 1 and 6) after a long reaction time. As previously observed [57,60], the conversion of 4,5-diamino cyclopentenone to 2,4-diamino cyclopentenone was performed in the presence of an excess of amine. To investigate the catalytic activity of MK10 and its selectivity, we tested the performance of trans-4,5-dimorpholinocyclopent-2-enone in the presence of a small amount of morpholine, to obtain 2,4-dimorpholinocyclopent-2-enone (Scheme 2). 2,4-Diamino cyclopent-2-enone, a by-product observed in the cyclization, was obtained at room temperature or in the absence of a catalyst ( Table 1, entries 1 and 6) after a long reaction time. As previously observed [57,60], the conversion of 4,5-diamino cyclopentenone to 2,4-diamino cyclopentenone was performed in the presence of an excess of amine. To investigate the catalytic activity of MK10 and its selectivity, we tested the performance of trans-4,5-dimorpholinocyclopent-2-enone in the presence of a small amount of morpholine, to obtain 2,4-dimorpholinocyclopent-2enone (Scheme 2). Adding the amine (0.2 mmol) to the reaction mixture at room temperature without microwave irradiation, we observed that the 4,5-dimorpholino cyclopentenone was converted into the respective 2,4-cyclopentenone derivative after only one hour. In fact, the presence of excess amines leads to the formation of an enolic intermediate that successively yields the respective 2,4-cyclopentenone derivative. The mechanism of this reaction was proposed by Lewis and Mulquiney [82].
All reactions were monitored by GC-MS. The GC-MS Shimadzu workstation was constituted by a GC 2010 equipped with a QUADREX 007-5MS (30 m × 0.25 mm, 0.25 µm) capillary column, operating in "split" mode with 1 mL·min −1 flow of He as the carrier gas. 1 H-NMR spectra were recorded on a Brüker spectrometer at 300 MHz. Chemical shifts are reported in δ units (ppm), with tretramethylsilane (TMS) as the reference (δ 0.00). All coupling constants (J) are reported in hertz. Multiplicity is indicated by one or more of the following: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). 13 C-NMR spectra were recorded on a Brüker spectrometer at 75 MHz. Chemical shifts are reported in δ units (ppm) relative to CDCl3 (δ 77.0). Adding the amine (0.2 mmol) to the reaction mixture at room temperature without microwave irradiation, we observed that the 4,5-dimorpholino cyclopentenone was converted into the respective 2,4-cyclopentenone derivative after only one hour. In fact, the presence of excess amines leads to the formation of an enolic intermediate that successively yields the respective 2,4-cyclopentenone derivative. The mechanism of this reaction was proposed by Lewis and Mulquiney [82].
All reactions were monitored by GC-MS. The GC-MS Shimadzu workstation was constituted by a GC 2010 equipped with a QUADREX 007-5MS (30 m × 0.25 mm, 0.25 µm) capillary column, operating in "split" mode with 1 mL·min −1 flow of He as the carrier gas. 1 H-NMR spectra were recorded on a Brüker spectrometer at 300 MHz. Chemical shifts are reported in δ units (ppm), with tretramethylsilane (TMS) as the reference (δ 0.00). All coupling constants (J) are reported in hertz. Multiplicity is indicated by one or more of the following: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). 13 C-NMR spectra were recorded on a Brüker spectrometer at 75 MHz. Chemical shifts are reported in δ units (ppm) relative to CDCl 3 (δ 77.0). MW-assisted reactions were performed on a Synthos 3000 instrument from Anton Paar (Graz, Austria), equipped with a 4 × 24MG5 rotor, with an IR probe used for external temperature control.

General Experimental Procedure for the Microwave-Assisted Cyclical Rearrangement of Furfural and Amines
Morpholine (2 mmol) was added to a stirred solution of furfural (1 mmol) and MK10 (20 mg). The resulting mixture was reacted for 5 min in a Synthos 3000 microwave instrument, fixed at a temperature value of 60 • C (IR limit).
After completion of the reaction (monitored by GC-MS), the MK10 was separated from the reaction mixture by filtration, and washed with ethyl acetate (3 mL) four times. The products were isolated after evaporation of the solvent to yield compounds at an efficiency of 90-99%. Spectral data were in accordance with the literature [61].
The reaction of morpholine with furfural was scaled up to grams, using 20 mmol of furfural and 40 mmol of morpholine, with amounts corresponding to MK10. After completion of the reaction and separation of MK10, the product was obtained with a yield of 97%. All the characterization data are available in Supplementary Materials.

General Protocol for the Synthesis of 2,4-Diamorpholinecyclopent-2-enones
After the formation of trans-4,5-dimorpholinocyclopen-2-enone following the reported procedure, we added 0.2 mmol of morpholine to the mixture, and kept the reaction at room temperature for a further hour. After completion, ethyl acetate was added (3 mL), the catalyst was filtered, and the product was isolated after evaporation of the solvent to afford 2,4-dimorpholinecyclopent-2-enone at 99% yields. Spectral data were in agreement with the literature [61].

Catalyst Recycling
The MK10 obtained was further evaluated in the cyclization reaction of furfural and morpholine. As shown in Figure 1, after four runs, the selectivity still remained above 99%, and the conversion was only slightly reduced.

Conclusions
An effective procedure for the synthesis of trans-4,5-diamino-cyclopent-2-enones has been developed. The reaction showed a high degree of conversion and selectivity.
The use of MK10 under MW irradiation is a valuable method of for the use of a heterogeneous catalyst, as compared to previously reported procedures: the performance does not allow for the use of a solvent, the reaction times are very short, and a greater degree of selectivity in the rearrangement process occurs, thus avoiding the formation of by-products.
Additional advantages of this method are the use of a recyclable heterogeneous catalyst that is stable for the next run. MK10 was reused for three consecutive cycles without any significant loss in catalytic activity for the synthesis of trans-4,5-dimorpholine-cyclopent-2-enones.

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