BF₃/nano-sawdust as a green, biodegradable and inexpensive catalyst for the synthesis of highly substituted dihydro-2-oxopyrroles

Abstract

BF₃/nano-sawdust was used as a readily available, inexpensive, biodegradable and environmentally benign heterogeneous solid acid catalyst for the one-pot cascade synthesis of highly functionalized dihydro-2-oxypyrroles. Four-component reactions (4CRs) of dialkylacetylenedicarboxylates, primary amines and aldehydes were used for the synthesis of these compounds under thermal conditions.

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Introduction

Dihydro-oxopyrrole (DPO) derivatives are important structures that exhibit biological activities such as herbicidal,¹ antitumor,² pesticidal,³ anti-HIV,⁴ antibiotic⁵ and antimalarial,⁶ and its derivatives are crucial core structures used to create many natural products such as bilirubins,⁷ oteromycin,⁸ ypaoamide⁹ and pyrrocidine A¹⁰ (Scheme 1).

Scheme 1 The structure of some natural compounds with the dihydro-2-oxopyrrole motif.

Due to the wide range in applications of dihydro-oxopyrrole derivatives in pharmaceuticals, agrochemicals, and natural products, their synthesis remains an area of intense current interest. A number of synthetic routes have been developed for the synthesis of dihydro-oxopyrrole, including the ruthenium-catalyzed reaction of α,β-unsaturated imines with carbon monoxide and ethylene,¹¹ the reaction of isocyanides, dialkylacetylenedicarboxylates, and benzoyl chlorides,¹² the carboamination/oxidative cyclization of C-acylimines with alkenes,¹³ the transannulation of 1-sulfonyl-1,2,3-triazole with ketene silylacetal,¹⁴ the reaction of acetylene with imines and CO₂,¹⁵ the Pd-catalyzed cyclization of ethyl glyoxalate and amines¹⁶ and the reaction of α-cyanomethyl-β-ketoesters and alcohols.¹⁷ Among these versatile synthetic methods, multicomponent reactions (MCRs) have attracted particular attention;¹⁸ a few methods have been reported for the synthesis of dihydro-2-oxopyrroles using MCRs such as the four-component reaction of dialkylacetylenedicarboxylate, aldehyde, and amines. Previously, this protocol has been catalyzed by TiO₂-nanopowder,¹⁹ I₂,²⁰ p-toluenesulfonic acid,²¹ Cu(OAc)₂·H₂O/salicylic acid,²² AcOH,²³ 1-methyl-2-oxopyrrolidinium hydrogen sulfate ([Hpyro][HSO₄]),²⁴ InCl₃²⁵ and [n-Bu₄N][HSO₄].²⁶

Some of these catalysts have many limitations such as the inefficient separation of the catalyst from homogeneous reaction mixtures,^20–23 unrecyclability and environmental limitations.^20–25 Hence, the development of new solid acids with numerous advantages such as cost-effectiveness, environmental benignity, easy workup and good stability for the one-pot multicomponent synthesis of highly substituted dihydro-oxopyrrole scaffolds is still in demand. In this regard, our aim is to develop cheap biopolymeric solid acid catalysts for this transformation.

Cellulose is one of the most abundant natural carbon-based biopolymers containing free OH groups with nucleophilic character. It has been used for the synthesis of some compounds that are used in enantioselective chromatography,²⁷ protein immobilization,²⁸ antibodies²⁹ and retarded drug release.³⁰

Sawdust is a biodegradable, natural, cheap, renewable and readily available source of cellulose.

In this work, we have investigated the synthesis of a sawdust-based catalyst by bonding Lewis acids to the OH groups of D-glucose units. Sawdust contains cellulose with other substances such as pectin, tannin, proteins, minerals and lignin that caused leaching in organic media. Therefore, the pectin, lignin, proteins and minerals must be removed. For this purpose the pine sawdust was treated with NaOH, NaClO, and H₂O₂. For the preparation of nano-sawdust, the sawdust was treated with concentrated H₂SO₄ for the partial hydrolysis of its cellulose. Then, the nano-sawdust was used in the synthesis of BF₃/nano-sawdust as a new, biodegradable and green catalyst.

We wish to report herein its catalytic behavior for the cost-effective and facile one-pot cascade synthesis of highly functionalized dihydro-2-oxopyrroles via 4CRs of dialkylacetylenedicarboxylates, amines and aldehyde under thermal conditions.

Results and discussion

In order to investigate the structure of BF₃/nano-sawdust, we have studied the FT-IR (ATR) spectra of pine sawdust and BF₃/nano-sawdust (Fig. 1). In the sawdust FT-IR spectrum, two strong bands at 3331 and 1020 cm⁻¹ were observed. In the BF₃/nano-sawdust, in addition to the bands mentioned above, some bands also appeared at 820, 913, 1264, 1424 and 1633 cm⁻¹. The band at 916 cm⁻¹ verifies the C–O–B group within BF₃/nano-sawdust.

Fig. 1 FT-IR (ATR) spectrum of (a) pine sawdust and (b) BF₃/nano-sawdust.

The proposed structure containing a possible model for acid sites formed on the catalyst is similar to the reported structure for cellulose triphosphate gels that were prepared by the phosphorylation of trihydroxy³¹ groups of D-glucose units and BF₃/γ-Al₂O₃ (Scheme 2).³²

Scheme 2 Proposed structure for (a) BF₃/nano-sawdust, (b)BF₃/γ-Al₂O₃ and (c) cellulose triphosphate.

The FESEM images of nano-sawdust and BF₃/nano-sawdust are shown in Fig. 2. According to the FESEM data, the size of the catalyst particles is below 50 nm. Quantitative elemental information (EDS) of BF₃/nano-sawdust was measured using a SEM/EDS instrument, Phenom pro X, (Fig. 3). According to this data, the weight percentage of F, O and C are 46.4, 39.3 and 7.9, respectively.

Fig. 2 FESEM images of (a) nano-sawdust and (b) BF₃/nano-sawdust.

Fig. 3 EDS analysis diagram of BF₃/nano-sawdust.

The amount of boron in the catalyst was determined. For this purpose, a mixture of BF₃/nano-sawdust (0.5 g) and water (50 mL) was stirred and boiled for 1 hour. Then, the mixture was cooled and titrated with 12.5 mL of standard NaOH (0.18 N) in the presence of phenolphthalein. The amount of boron in the catalyst was found to be 5.5 meq. g⁻¹. In this process, the boron attached to the cellulose reacted with water, captured OH⁻ from water and produced H⁺ that corresponded to the OH⁻ (Scheme 3).

Scheme 3

The thermal gravimetric analysis (TG-DTG) curve for BF₃/nano-sawdust was measured from 20 to 515 °C (Fig. 4). The catalyst is stable until 55 °C and only 15% of its weight was reduced at 115 °C due to the removal of catalyst moisture. Heating the catalyst until 515 °C, caused 73% of its mass to be lost. The char yield of the catalyst at 515 °C was 30%. According to the TG-DTG diagram of BF₃/nano-sawdust and our study, it was revealed that this catalyst is suitable for the promotion of organic reactions below 115 °C.

Fig. 4 Thermal gravimetric analysis (TG-DTG) curve for BF₃/nano-sawdust.

In this study, we have investigated the catalytic activity of BF₃/nano-sawdust for the synthesis of dihydro-2-oxopyrroles via 4CRs of dialkylacetylenedicarboxylates, amines and aldehyde.

The synthesis of dihydro-2-oxopyrroles is a kind of intermolecular nucleophilic addition reaction (Mannich reaction type) with several intermediates. Therefore, it is necessary to choose suitable conditions such as catalyst, solvent and temperature for this reaction. As a model reaction, the synthesis of methyl-1-(4-chlorophenyl)-4-((4-chlorophenyl)amino)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate was examined under various conditions in the presence of BF₃/nano-sawdust as a catalyst (Table 1). As shown in Table 1, the highest yield of the reaction was acquired using 3 mmol of formaldehyde in ethanol at 70 °C and in the presence of 0.08 g BF₃/nano-sawdust after 3.5 h (Table 1, Entry 8). The effect of different solvents on the reaction was investigated and it was revealed that ethanol gave the best results for this transformation. It was noted that when the reaction was performed in the same conditions mentioned in entry 8 without the catalyst, the desired product was obtained in low yield (Table 1, Entry 13). The reusability of the catalyst was investigated over three cycles (Table 1, Entries 14–16). For this purpose, after each run the reaction mixture was diluted with acetone or ethanol and filtered to isolate the catalyst. The obtained catalyst was then washed with chloroform followed by drying at room temperature. The recovered catalyst was then used for the next run of the reaction. It was found that the reactivity of the catalyst decreases marginally for the next run (approx. 3%).

Table 1 Preparation of methyl-1-(4-chlorophenyl)-4-((4-ethylphenyl)amino)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylate under various conditions^a

Entry	Solvent	Catalyst	Reactant I : II : III	Condition	Time	Yield^b
a Reactions were run using the following steps: (a) dimethylacetylendicarboxylate (1 mmol) and 4-chloroaniline (1 mmol) were added into 4 mL of the solvent and kept at room temperature for 15 min; (b) 4-chloroaniline (1 mmol), formaldehyde and the indicated mass in g or proportion of the catalyst were added to the above mixture, and then stirred at rt/70 °C for the desired time.b Isolated yield after recrystallization from ethanol.c Diethylacetylenedicarboxylate instead of dimethylacetylenedicarboxylate was used.d 4-Bromoaniline instead of 4-chloroaniline was used.
1	EtOH	—	2 : 1 : 1.5	R.T.	3 h	—
2	EtOH	BF3/nano-sawdust (0.06)	2 : 1 : 1.5	R.T.	3 h	14%
3	EtOH	BF3/nano-sawdust (0.08)	2 : 1 : 1.5	R.T.	3 h	17%
4	EtOH	BF3/nano-sawdust (0.08)	2 : 1 : 1.5	Reflux	3 h	37%
5	EtOH	BF3/nano-sawdust (0.08)	2 : 1 : 2	Reflux	3 h	52%
6	EtOH	BF3/nano-sawdust (0.08)	2 : 1 : 2.5	Reflux	3 h	62%
7	EtOH	BF3/nano-sawdust (0.08)	2 : 1 : 2.5	Reflux	3.5 h	81%
8	EtOH	BF3/nano-sawdust (0.08)	2 : 1 : 3	Reflux	3.5 h	92%
9	MeOH	BF3/nano-sawdust (0.08)	2 : 1 : 3	Reflux	3.5 h	60%
10	EtOH/MeOH 1 : 1	BF3/nano-sawdust (0.08)	2 : 1 : 3	Reflux	3.5 h	67%
11	CHCl3	BF3/nano-sawdust (0.08)	2 : 1 : 3	Reflux	3.5 h	24%
12	n-Hexane	BF3/nano-sawdust (0.08)	2 : 1 : 3	Reflux	3.5 h	38%
13	EtOH	—	2 : 1 : 3	Reflux	3.5 h	20%
14	EtOH	BF3/nano-sawdust (0.08), 2^nd run	2 : 1 : 3	Reflux	3.5 h	90%
15	EtOH	BF3/nano-sawdust (0.08), 3^rd run	2 : 1 : 3	Reflux	3.5 h	87%
16	EtOH	BF3/nano-sawdust (0.08), 4^th run	2 : 1 : 3	Reflux	3.5 h	84%
17	MeOH	[n-Bu4N][HSO4] (10 mol%)	2 : 1 : 1	R.T.	4 h	86%^26
18	MeOH	InCl3 (20 mol%)	2 : 1 : 1.5^c	R.T.	3 h	79%^25
19	EtOH	AcOH (2 eq.)	3 : 1 : 1.5^d	Reflux	4 h	89%^23

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Finally, with the optimized reaction conditions obtained for the synthesis of IV, the scope of this transformation was explored regarding the amount of reactant, solvent, amount of catalyst and reaction temperature. Accordingly, the synthesis of different dihydro-2-oxopyrrole derivatives was examined and high yields were noticed in most of the cases (Table 2).

Table 2 Synthesis of dihydro-2-oxopyrrole derivatives in the presence of BF₃/nano-sawdust at 70 °C^a

Entry	R^1	R^2	R^3	Product	Time	Yield^b	M.P. (Ref.)
a For entries 1–13 and 18, the ratio of amine (mmol) : dialkylacetylenedicarboxylate (mmol) : formaldehyde (mmol) : BF3/nano-sawdust (g) was 2 : 1 : 3 : 0.08. For entries 14–17, the ratio of amine (mmol) : dialkylacetylenedicarboxylate (mmol) : aldehyde (mmol) : BF3/nano-sawdust (g) was 2 : 1 : 2 : 0.08.b Isolated yields after recrystallization from ethanol. R^4CHO was formaldehyde for entries 1–13 and 18, benzaldehyde for entries 14 and 16–17, and 4-methylbenzaldehyde for entry 15.
1	4-Me-C6H4	Me	4-Me		4 h	84%	175–176 (ref. 22)
2	4-Me-C6H4	Et	4-Me		4 h	88%	128–130 (ref. 23)
3	4-Et-C6H4	Me	4-Et		4 h	81%	125–126 (ref. 20)
4	4-Et-C6H4	Et	4-Et		4 h	80%	98–100
5	4-OMe-C6H4	Me	4-OMe		5 h	83%	160–162 (ref. 20)
6	4-OMe-C6H4	Et	4-OMe		5 h	85%	152–154 (ref. 25)
7	4-Br-C6H4	Me	4-Br		3 h	90%	181–182 (ref. 22)
8	4-Br-C6H4	Et	4-Br		3 h	91%	165–166 (ref. 22)
9	4-Cl-C6H4	Me	4-Cl		3.5 h	92%	173–174 (ref. 22)
10	4-Cl-C6H4	Et	4-Cl		3 h	95%	165–167 (ref. 26)
11	3-NO2-C6H4	Me	3-NO2		2 h	79%	204–206
12	3-NO2-C6H4	Et	3-NO2		2 h	85%	191–192
13	4-NO2-C6H4	Et	4-NO2		3 h	75%	206–208
14	4-Cl-C6H4	Me	4-Cl		3.5 h	89%	175–177 (ref. 22)
15	4-Cl-C6H4	Me	4-Cl		4 h	92%	148–150 (ref. 19)
16	PhCH2	Me	4-Cl		3 h	88%	136–138 (ref. 22)
17	PhCH2	Me	4-Br		3 h	91%	154–156 (ref. 22)
18	PhCH2	Et	H		4 h	95%	138–140 (ref. 23)

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Experimental section

Materials and methods

All chemicals and solvents were purchased from the Merck and Fluka Chemical Companies in high purity. Materials used were at commercial reagent grade. FT-IR spectra were recorded on an attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectrophotometer (Bruker, Eqinox 55). ¹H NMR and ¹³C NMR spectra were recorded at 400 MHz and 100 MHz, respectively, on a BrukerDXR-400 spectrometer using CDCl₃ as solvent and tetramethylsilane as the internal standard. Mass spectra (MS) were recorded on a FINNIGAN-MAT 8430 mass spectrometer, operating at an ionization potential of 70 eV. Melting points were obtained with a Büchi melting point apparatus (B-540 BÜCHI). Quantitative elemental information (EDS) of BF₃/nano-sawdust was measured using a SEM/EDS instrument (Phenom pro X).

Preparation of nano-sawdust

Pine sawdust (4 g) was first treated with a solution of 17.5% w/v sodium hydroxide in a water bath maintained at 100 °C for 12 hours to remove tannin, pectin, proteins and minerals. The residue was alpha cellulose that was not soluble in the 17.5% w/v sodium hydroxide solution. The alkali-treated fibers were washed repeatedly. The stock was then bleached with 100 mL of 1 : 1 dilution 5% w/v sodium hypochlorite solution at 80 °C for 8 h. The resulting mixture was then treated with 10 mL of 20% v/v hydrogen peroxide at 50 °C for 2 hours to remove the insoluble lignin. The resulting mixture was hydrolyzed by refluxing with sulfuric acid (65% H₂SO₄ with a fiber to liquor ratio of 1 : 20) for 2 hours at 60 °C with strong agitation. The resulting mixture was cooled to room temperature and diluted by adding an excess of distilled water. The suspension was then repeatedly centrifuged at 12 000 rpm for 8 minutes using a refrigerated centrifuge (Eppendorf Centrifuge 5417R). After each run, the nano-sawdust (as white powder) was washed with distillated water and centrifuged until the supernatant was neutral.

Preparation of BF₃/nano-sawdust

In a ventilated room, to a 25 mL suction flask equipped with a constant-pressure dropping funnel containing BF₃·Et₂O (1 mL) and a gas inlet tube for conducting HF, charged with 1 g nano-sawdust and chloroform, BF₃·Et₂O was added dropwise over a period of 3 min at room temperature. The mixture was stirred for one hour at room temperature. The resulting mixture was filtered. The obtained white solid was washed with chloroform and dried at room temperature.

Typical procedure for the synthesis of dihydro-2-oxopyrroles

In a round-bottom flask (50 mL) equipped with a reflux condenser, a mixture of substituted amine (1 mmol) and dialkylacetylenedicarboxylate (1 mmol) in absolute ethanol (4 mL) was stirred for 30 min. Then, the other substituted amine (1 mmol), formaldehyde 37% (3 mmol) or substituted benzaldehyde (2 mmol) and BF₃/nano-sawdust (0.08 g) in absolute ethanol (3 mL) were added to the above mixture and stirred at 70 °C. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was allowed to cool, filtered off and washed with EtOH (3 × 10 mL) to remove all unreacted substrates. For the separation of the catalyst from the solid product, it was washed with chloroform (15 mL). The chloroform was evaporated and the crude solid product was recrystallized from ethanol to give the corresponding dihydro-2-oxopyrroles.

Conclusions

In summary, BF₃/nano-sawdust was introduced as a green, cheap, natural, biodegradable and readily available biopolymeric solid acid catalyst. We have shown that various substituted dihydro-2-oxopyrrole derivatives can be successfully synthesis by an operationally simple and highly efficient one-pot four-component procedure using BF₃/nano-sawdust. This protocol has many advantages including high conversions, low catalyst loading, low-cost, easy workup and operational simplicity, which makes this method more attractive.

Acknowledgements

The Research Council of Yazd University is gratefully acknowledged for financial support of this study.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra16625f

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