Cellulose sulfonic acid as a green, efficient, and reusable catalyst for Nazarov cyclization of unactivated dienones and pyrazoline synthesis

Abstract

A high yielding, eco-friendly and simple procedure for the synthesis of five membered carbo- and heterocycles through cellulose sulfonic acid (CSA) mediated electrocyclization processes has been developed. Cellulose sulfonic acid (CSA) not only was able to induce the cyclization of “unactivated” dienones generating cyclopentenoids; it was also able to trigger the cyclization of α,β-unsaturated hydrazones giving rise to pyrazolines in excellent yields under green reaction conditions. The ease of catalyst recovery and reusability, short reaction time, simple experimental and work-up procedure; compared to the conventional methods, makes this protocol practical, environmentally friendly and economically desirable. The cellulose-SO₃H (CSA) was characterized by FT-IR spectroscopy, powder X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM) analyses, and catalyst stability was judged by thermogravimetry/differential thermal analysis (TG/DTA). The catalyst can be recycled several times without significant loss of catalytic activity.

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Introduction

Catalysis by homogeneous Brønsted acids is crucial for the manufacturing of important chemicals such as alcohols, ethers, esters, and many starting materials for polymers and resins. However, their separation, recycling and neutralization in chemical processes are costly and highly demanding. Sulfate wastes are produced during the neutralization of the homogeneous acids, and further separation from the product results in substantial energy consumption and material loss: more than 15 million tons of H₂SO₄, for instance, is consumed as an unrecyclable catalyst each year. Consequently, the general criteria of a catalyst as a reusable material that can constantly accelerate a chemical reaction would not meet.¹

In recent years, a “green” strategy has been adapted in chemical processes, which requires the utilization of recyclable solid acids as substituents for unrecyclable homogenous analogs. Their ease of separation from liquid products by decantation or filtration and their multiple usages without neutralization could lead to low cost and more efficient processes that will meet increasingly stringent environmental standards and are economically viable.^1f–i A practical solid acid material for catalytic processes should maintain high stability and possess numerous protonic acid sites. Therefore, a great amount of research has been devoted to immobilization of sulfuric acid on solid supports that are comparable to their homogenous ones in terms of activity, stability and cost: mesoporous and amorphous silica,² mesoporous and amorphous carbon,³ and magnetic nanoparticles (MNPs)⁴ are arguably the most extensively investigated and emerged as excellent and ideal supports with significant industrial potentials. They owe extraordinary properties such as large specific surface area, readily dispersion in reaction solution, simple functionalization with various groups, and non-tedious separation by centrifugation and filtration.

Among a diverse range of biodegradable materials, such as chitosan,⁵ gluconic acid,⁶ xanthan sulfuric acid,⁷ starch sulfuric acid,⁸ sulfuric acid-modified PEG (PEG-OSO₃H),⁹ eggshell,¹⁰ and meglumine¹¹ that have been exploited as solid-support acid catalysts for acid-catalyzed transformations, chlorosulfonic acid supported on cellulose (CSA) is considered as one of the best candidates for the design and development of green methods for the synthesis of biologically important compounds. Cellulose is viewed as one of the most chemically uniform and abundant biopolymers made by nature, and one of the unlimited sources of raw materials for environmentally friendly processes.¹² Given numerous reports utilizing cellulose sulfonic acid as a solid Brønsted acid catalyst in a variety of acid-catalyzed processes such as multicomponent transformations and condensation reactions¹³ cycloaddition,¹⁴ diazotization,¹⁵ and dehydration reactions,¹⁶ application of this environmentally benign catalyst in other useful synthetic transformations is still missing.

Electrocyclization processes are considered a common protocol for rapid assembly of five-membered carbo- and heterocycles in medicinally important molecules and natural product synthesis. These reactions that involve the concerted rearrangement of bonding electrons have the advantage of low activation barriers resulting in mild reaction conditions.¹⁷ The Nazarov cyclization, discovered by Nazarov in 1941,^18,19 is an important example of an 4π electrocyclic ring closure and a well-established method for the generation of cyclopentenone rings from divinyl (or arylvinyl) ketones in the presence of Lewis²⁰ or Brønsted acids.²¹ In the past, the harsh reaction conditions (strong acids, high temperatures, and high catalyst loading) and poor regioisomeric control required for the Nazarov reaction delayed its synthetic utilities.¹⁹ Although Lewis acids have been successfully utilized under catalytic conditions, some are only restricted to polarized or alkoxy substituted Nazarov substrates and in need of rigorous anhydrous reaction conditions.²⁰ However, the ubiquitous presence of five-membered carbocycles among natural products²² has stimulated massive research effort to solve these problems and strategies such as “directed Nazarov cyclization”,²³ the “interrupted Nazarov reaction”,²⁴ and employing a number of divinylketone equivalents or pentadienyl cation precursors which undergo cyclization under milder conditions²⁵ have been adopted. Despite these developments, only a very few Nazarov reactions using a catalytic amount of Brønsted acid have been conducted and they are mainly limited to oxygen-substituted or polarized dienones.²⁶ To the best of our knowledge there have not been any reports of using cellulose sulfonic acid as a recyclable biopolymeric catalyst for the acid-catalyzed Nazarov cyclization process and its synthetic utility has never been explored.

Another valuable eletrocyclization processes is 6π electrocyclization of α,β-unsaturated hydrazones into the corresponding five-membered heterocyclic pyrazolines.^17,27 These molecules exhibit potent biological activities, such as antidepressant, anticancer, anti-inflammatory, antibacterial, and antiviral activity.²⁸ Initially, Fischer recognized this practical acid-mediated process, and Huisgen later noted the isoelectronic relationship between this transformation and the 6π electrocyclization of the pentadienyl anion.^29,30 The [2 + 3]-dipolar cycloaddition of diazoalkanes and α,β-unsaturated carbonyl compounds is also another pathway to such motifs.³¹ Yet, Fischer's method is still considered as the most efficient approach for the preparation of these heterocyclic compounds.³²

The cellulose-SO₃H catalytic system constitutes the following features: (1) it adds favorably well with state-of-the-art results for the catalytic Nazarov cyclizations. (2) It was able to trigger the cyclization of non-oxygen-substituted or non-polarized dienones in excellent yields and short reaction time without resort to anhydrous conditions and inert atmospheres. (3) An environmentally friendly protocol for different electrocyclization processes avoiding harsh reaction conditions. (4) It is derived from cellulose-an unlimited source of raw materials made by nature along with its ease of recovery and reusability make this catalytic system practical and economically desirable. (5) The repeating structure of cellulose-SO₃H could result in spatial proximity of the acidic groups and greater acidic density enabling cooperative effect among acid sites that give rise to enhanced acidic strength.

We report herein a high yielding and environmentally friendly protocol for 4π electrocyclization of “unactivated” divinyl ketones and 6π electrocyclization of α,β-unsaturated hydrazones in the presence of cellulose sulfonic acid furnishing five-membered carbo- and heterocycles.

Experimental

General information

Reactions were carried out under air-conditioned environment. Solvents were distilled before use. Thin layer chromatography was performed on glass plates precoated with 0.25 mm Kieselgel 60 F254 (Merck). Flash chromatography column was packed with 230–400 mesh silica gel (Merck). Melting points were measured on an Electrothermal 9200 apparatus. Mass spectra were recorded on a Finnigan-MAT 8430 mass spectrometer operating at an ionization potential of 70 eV. Infrared (IR) spectra were recorded on a Shimadzu IR-470 spectrometer. Proton nuclear magnetic resonance spectra (¹H NMR) were recorded on a Bruker DRX-300 Avance spectrometer 300.13 MHz; chemical shifts (δ scale) are reported in parts per million (ppm) downfield from tetramethylsilane and referenced to residual protium in the NMR solvent (DMSO: δ 2.50, CDCl₃: δ 7.24). ¹H NMR spectra are reported in order: number of protons, multiplicity and approximate coupling constant (J value) in hertz (Hz); signals were characterized as s (singlet), d (doublet), t (triplet), m (multiplet) and br s (broad signal). The ¹³C NMR spectra were recorded at 75.47 MHz and 100 MHz; chemical shifts (δ scale) are reported in parts per million (ppm). The elemental analyses were performed with an Elementar Analysen systeme GmbH VarioEL. Diffraction data were collected on a STOE STADI P with scintillation detector, secondary monochromator and Cu-Ka1 radiation (λ = 1.5406 Å). TG/DTA experiments were carried out by a BÄHR Thermo analysis with a temperature program from 10 °C to 800 °C at a constant rate of 20 °C per min.

Preparation of cellulose sulfonic acid (CSA)

Cellulose sulfonic acid was prepared and characterized according to the known procedures.^13c,33 The catalyst was prepared by adding chlorosulfonic acid (1.00 g, 9 mmol) to a stirred mixture of cellulose (5.00 g, DEAE for column chromatography, Merck) in n-hexanes (20 mL) at 0 °C for 2 h. After complete addition, the mixture was stirred for additional 2 h. The mixture was filtered, washed with methanol and dried at room temperature to afford cellulose-SO₃H as white powder.

Titration analysis of cellulose-SO₃H

In order to access the number of H⁺ site of cellulose sulfonic acids, acid–base titration was carried out. 0.2 g of cellulose-SO₃H was dissolved in deionized water (10 mL) and the titration experiment was carried out in the presence of NaOH (0.1 N) and phenolphthalein as an indicator. Consequently the exact equivalence point of titration was found 0.3 mmol g⁻¹. A back titration strategy was also employed and no change in the number of H⁺ sites in cellulose-SO₃H was noticed (titration of other heterogenic acids was mentioned in ESI†).

General procedure for the cellulose-SO₃H catalyzed Nazarov cyclization

To a solution of divinyl ketone 1a–f (1 mmol) in EtOH (10 mL), cellulose sulfonic acid (0.4 g, 13 mol%) was added and the reaction was stirred at 60 °C for 12 h. After completion of the reaction, the reaction mixture was filtered to separate the catalyst. The solid catalyst was washed with EtOH (2 mL × 2), dried in oven at 60 °C and reused for further catalytic cycles. The filtrate was concentrated under reduced pressure, and the crude compound was purified by thin layer chromatography performed on glass plates pre-coated with silica (2 : 18, EtOAc/hexanes) to afford the desired Nazarov products 2a–f.

General procedure for the cellulose-SO₃H catalyzed pyrazoline synthesis

To a suspension of (3a–f) (1 mmol) and cellulose sulfonic acid (0.3 g, 10 mol%) in EtOH (10 mL), phenylhydrazine (0.21 g, 2 mmol) was added and stirred at 60 °C. After completion of the reaction which was monitored by TLC, the mixture was poured into cold water and the precipitate was filtered, subsequently, ethyl acetate was added to the precipitate in order to dissolve the product and then was filtered to separate the catalyst. The solid catalyst was washed with EtOH (2 mL × 2), dried in an oven at 60 °C and reused for further catalytic cycles. The filtrate was concentrated under reduced pressure and purified by recrystallizing from ethanol and dried under high vacuum to afford the desired products (5a–f).

Results and discussion

Preparation and characterization of cellulose-SO₃H

The catalyst was prepared by adding chlorosulfonic acid to a stirred mixture of cellulose in n-hexanes.³³ The number of H⁺ sites on cellulose sulfonic acid was determined by acid–base back titration experiment and found to be 0.3 mmol g⁻¹ while the sulfur content of the samples was 0.35 mmol g⁻¹ as judged by conventional elemental analysis. The similarity between these two values indicated that the most of the sulfur species in the sample was part of the sulfonic acid groups.

The FT-IR spectrum of the catalyst showed a broad peak for an OH absorption band at the peaks at 3440 cm⁻¹. Peaks at 1158, 1055, and 904 cm⁻¹ indicated C–O stretching, C–C skeletal vibration, and C₁–H ring stretching of the glucose unit, respectively.³⁴ The three new bands appeared in FTIR spectrum at 1163, 1048, and 674 cm⁻¹ corresponding to the O=S=O asymmetric and symmetric stretching vibrations and S–O stretching vibration of the sulfonic acid groups (Fig. 1a).³⁵ The powder XRD pattern (Fig. 1b) of the matrix showed characteristic diffraction peaks for the cellulose entity at 16.5, 22.5 and 34°.³⁶ The SEM micrographs (Fig. 1c) were used to study surface morphology of cellulose sulfonic acid and a homogeneous fibrous surface was observed. To assess the thermal stability of cellulose sulfonic acid (CSA), TG/DTA experiments were carried out and the thermograms are illustrated in Fig. 1d. The weight losses found by TGA measurements agreed well with those anticipated for the decomposition of cellulose sulfonic acid to cellulose and the sulfonic acid group. As shown in Fig. 1d the TG curve seems to indicate a three-stage decomposition with a weight loss of 11.52% between 73.17 °C and 123.28 °C which could be assigned to the evaporation of surface-physisorbed water. Another weight loss of 30.30% between 291.37–399.43 °C could be due to the decomposition of the loaded sulfuric acid along with the cellulose polymer and the third weight loss of 26.70% between 467.78–534.71 °C could be attributed to the decomposition of cellulose.³⁷ The DTA measurements provide further evidence for the loss of physisorbed water and loaded sulfonic acid moiety on the cellulose (see ESI†).

Fig. 1 (a) FT-IR spectra of (i) cellulose and (ii) cellulose-SO₃H. (b) Powder XRD of (i) cellulose, (ii) cellulose-SO₃H. (c) SEM image of the fresh catalyst (cellulose-SO₃H). (d) TG analysis of (i) cellulose and (ii) cellulose-SO₃H.

Catalytic activity of cellulose sulfonic acid

Except some few reports utilizing green strategies such as silica gel mediated Nazarov cyclization³⁸ and solvent-free Nazarov cyclization under microwave irradiation,³⁹ there have been only two examples of Nazarov reaction utilizing solid acids as catalyst: Pale and co-workers⁴⁰ reported zeolite promoted cyclization of arylvinyl ketones in good yields for less reactive substrates under harsh reaction conditions that employs stoichiometric amount of solid acid while in another report, Chen and co-workers⁴¹ described heteropolyacids (HPAs) for the cyclization of mostly reactive and polarized dienones in acetonitrile at 40 °C. Since the development of mild acid promoters for non-oxygen-substituted or non-polarized dienones could play a significant role in the development of the Nazarov cyclization as an important synthetic methodology; we envisioned that cellulose sulfonic acid, as a recyclable solid Brønsted acid might be able to promote the Nazarov cyclization of simple unactivated dienones under mild reaction conditions.

Initial attempt was focused at Nazarov cyclization of dienone 1a as the model compound in the presence of different Brønsted acids in ethanol at moderate heating (60 °C). We screened a variety of Brønsted acid catalysts and solvents at different reaction times, temperatures, and catalyst loadings that are all summarized in Table 1. As was expected the cyclization did not proceed in the presence of cellulose while homogenous strong Brønsted acids such as hydrogen chloride, p-toluene sulfuric acid, and camphor sulfuric acid did not induce the Nazarov cyclization of the model compound either. A modest improvement in yield and selectivity was obtained using mesoporous silica functionalized sulfonic acids (Table 1, entry 6 and 7) while the best result was obtained in the presence of cellulose sulfonic acid and the substrate scope was investigated using the latter catalyst.⁴²

Table 1 Optimization for the synthesis of 2-cyclopentenone 2a^a

Entry	Catalyst	Time (h)	T (°C)	Solvent	X (mol%)	Yield (%)	trans/cis^d (%)
a Reaction conditions: 1a (1 mmol), solvent (10 mL).b Determined by ^1H NMR spectroscopy, using anisol as internal standard.c Isolated yield.d The ratio of diastereomers was determined by ^1H NMR spectroscopy.
Effect of catalyst
1	Cellulose sulfonic acid	0.75	60	EtOH	13	97^b	60/40
2	pTSA	0.75	60	EtOH	13	No reaction	—
3	HCl	0.75	60	EtOH	13	No reaction	—
4	Camphor sulfonic acid	0.75	60	EtOH	13	No reaction	—
5	L-Proline	0.75	60	EtOH	13	No reaction	—
6	Silica sulfonic acid	0.75	60	EtOH	13	25^b	80/20
7	MCM-41 sulfonic acid	0.75	60	EtOH	13	26^b	61/39
8	Galactose sulfonic acid	0.75	60	EtOH	13	6^b	56/34
9	SBA-15 sulfonic acid	0.75	60	EtOH	13	7^b	45/55
10	Cellulose	0.75	60	EtOH	13	No reaction	—
Effect of catalyst loading
11	None	24	60	EtOH	0	No reaction	—
12	Cellulose sulfonic acid	4	60	EtOH	3	40^c	—
13	Cellulose sulfonic acid	2	60	EtOH	6	51^c	—
14	Cellulose sulfonic acid	1.2	60	EtOH	9	83^c	—
15	Cellulose sulfonic acid	0.75	60	EtOH	13	97^c	—
16	Cellulose sulfonic acid	0.75	60	EtOH	16	90^c	—
Effect of solvent and temperature
17	Cellulose sulfonic acid	24	RT	EtOH	13	No reaction	—
18	Cellulose sulfonic acid	6	40	EtOH	13	No reaction	—
19	Cellulose sulfonic acid	0.75	60	EtOH	13	97^c	—
20	Cellulose sulfonic acid	0.75	70	EtOH	13	97^c	—
21	Cellulose sulfonic acid	1	60	Toluene	13	No reaction	—
22	Cellulose sulfonic acid	1	40	CHCl3	13	No reaction	—
23	Cellulose sulfonic acid	1	40	CH2Cl2	13	No reaction	—
24	Cellulose sulfonic acid	1	40	Acetone	13	No reaction	—
25	Cellulose sulfonic acid	0.75	60	MeOH	13	80^c	—
26	Cellulose sulfonic acid	1	60	DMF	13	No reaction	—
27	Cellulose sulfonic acid	1	60	THF	13	No reaction	—
28	Cellulose sulfonic acid	1	60	MeCN	13	60^c	—

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Variation of the catalyst loading had a great effect on the catalytic activity (Table 1, entries 11–16). In the absence of the catalyst the reaction did not proceed even after 24 hours. When the reaction was carried out using 3.0, 6.0, and 9.0 mol%, both the rate of reaction and the chemical yields were evenly increased. However, the best result was observed using 13 mol% catalyst at 60 °C providing the product in 97% yield in 45 minutes. A further increase in the catalyst loading slightly decreased the chemical yield of the desired product while the rate of the reaction remained constant (see ESI†). From mechanistic viewpoint, all the acidic sites of the catalyst with the loading of 13 mol% are employed for the activation of the substrate. Hence, increase in catalyst loading to 16 mol% does not have a significant effect on the activation of the substrate.

The reaction did not proceed at room temperature even after 24 h, while heating the reaction to 70 °C induced the cyclization furnishing the cyclopentenone 2a in 97% yield. The best yield was observed when the reaction was performed at 60 °C. Increasing or decreasing the temperature from 60 °C attenuated the reaction yield (Table 1, entries 17, 19, 20 and 25). The impact of different solvents on the reaction yield was also examined, and the best result was obtained in EtOH as an environmentally benign solvent (Table 1, entry 20).

We also detected a slight epimerization of the cis isomer to the thermodynamically more favored trans isomer. Although the reaction was completed after 45 minutes with a trans/cis (60 : 40) diastereomeric ratio favoring the trans isomer, increasing the reaction time to 12 h induced the cis to trans epimerization, resulting a better diasteromeric ratio (66 : 34). Ultimately, the Nazarov cyclization proceeded very well in EtOH at 60 °C and the desired cyclopentenone adduct 2a was obtained in 97% yield in the presence of chlorosulfonic acid supported on biomass-derived biopolymer. The efficiency of the cellulose-SO₃H catalyst could be related to the degree of substitution (DS) with OH groups, and multiple acidic sites on the polymeric backbone and also to greater surface area and fine dispersion of the catalyst on the surface of cellulose which was supported by the lack of efficiency in the case of galactose cellulose-SO₃H (Table 1, entry 8).

Having optimized the conditions, we set to explore the reactivity of unreactive dienones for the Nazarov cyclization prepared under a simple aldol condensation (see ESI†).

Dienone 1a–f underwent a smooth cyclization under the conditions employed, providing cyclized products 2a–f in excellent yields and a modest to excellent diastereomeric ratios (dr) depending on the substitution pattern of the divenyl ketones. Installation of an electro-withdrawing chloride group onto the ortho-position of the phenyl ring (1b) did not diminish the reaction yield, while it increased the diastereomeric ratios (dr = 84 : 16) presumably due to the increasing steric demand of the chloro-phenyl substituent. Surprisingly, the installation of the second chloride group onto the ortho position (1c) inverted the selectivity favoring the cis isomer (dr = 21 : 79) suggesting the phenyl substituent might adopt an orthogonal orientation with respect to the methyl group. Cyclization of the sterically hindered substrate with α-phenyl substituent (1f) proceeded smoothly with good induction, furnishing a single diastereomer in high yield with complete diastereoselectivity that was further confirmed via an NOE experiment (see ESI†). Divenyl ketones with sensitive furan and thiophene substituents (1d and e) were stable under the present conditions providing cyclopentenones 2d and 2e in 91% and 92% yields, respectively. The yield, reaction time, and conditions in the presence of cellulose-SO₃H are superior to those of other catalysts used for similar transformation (Table 2).

Table 2 Nazarov cyclization of different divinyl ketones 1 in the presence of cellulose-SO₃H

Entry	Substrate	Product^a	Yield^b^,^c (%)	trans/cis^d (%)
a Reaction conditions: substrates (1 mmol), catalyst (13 mol%), EtOH (10 mL).b Isolated yield.c All products were characterized by comparison of their ^1H NMR and ^13C NMR spectra with those of authentic samples (see ESI).d trans and cis isomers were identified by comparison with the literature data and their ratio was determined by ^1H NMR spectroscopy.
1			97	66/34
2			96	84/16
3			95	21/79
4			91	53/47
5			92	75/25
6			95	100

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The plausible mechanism of a Nazarov cyclization is shown in Scheme 1. The reaction is initiated by the reversible coordination of cellulose-SO₃H as a solid Brønsted acid to the dienone substrate triggering the electrocyclization of the pentadienyl cation I. The key step of the reaction mechanism involves a cationic 4π electrocyclization process that proceeds through a conrotatory closure forming an oxyallyl cation II having an anti relationship between R₂ and R₄ substituents. This step is usually followed by a loss of proton from cation III, to give a single or a mixture of diastereomeric cyclopentenone products. The trans stereochemistry between R₃ and R₄ is due to the formation of the thermodynamically more stable product.

Scheme 1 Plausible mechanism for the Brønsted acid-catalyzed Nazarov reaction.

Encouraged by the remarkable results and having established that cellulose-SO₃H constitutes an active catalyst for the Brønsted acid catalyzed 4π electrocyclization process, we extended this protocol to another electrocyclization process catalyzed by a Brønsted-acid that involves a 6π electrocyclization of α,β-unsaturated hydrazones into the corresponding pyrazolines.

Recently, Holla and co-workers reported a heterogeneous Amberlyst-15 promoted cyclization of α,β-unsaturated ketones in the presence of hydrazines under the reflux toluene conditions for two days affording pyrazoline derivatives in moderate yield.⁴³

Dibenzylideneacetone 3a in the presence of phenyl hydrazine 4 as the model compound has been used to investigate the 6π electrocyclization process leading to pyrazoline 5a. We screened a variety of solid Brønsted acid catalysts and solvents at different reaction times, temperatures, and catalyst loadings that are all summarized in Table 3. As was anticipated the cyclization did not proceed in the presence of cellulose (Table 3, entry 1) while poor yields was obtained in the presence of galactose sulfonic acid, amorphous and mesoporous silica functionalized sulfonic acids (Table 3, entries 2–4). The best result was obtained in the presence of cellulose sulfonic acid (Table 3, entry 5) and the substrate scope was investigated using the latter catalyst.

Table 3 Optimization for the synthesis of pyrazoline 5a^a

Entry	Catalyst	Time (h)	T (°C)	Solvent	X (mol%)	Yield^b (%)
a Reaction conditions: 3a (1 mmol), solvent (10 mL).b Isolated yield.
Effect of catalyst
1	Cellulose	24	60	EtOH	10	11
2	Galactose sulfonic acid	2	60	EtOH	10	21
3	Silica sulfonic acid	2	60	EtOH	10	29
4	MCM-41 sulfonic acid	2	60	EtOH	10	34
5	Cellulose sulfonic acid	2	60	EtOH	10	96
Effect of catalyst loading
6	None	48	60	EtOH	0	5
7	Cellulose sulfonic acid	4	60	EtOH	2	15
8	Cellulose sulfonic acid	3	60	EtOH	5	45
9	Cellulose sulfonic acid	2	60	EtOH	10	96
10	Cellulose sulfonic acid	2	60	EtOH	13	96
Effect of solvent and temperature
10	Cellulose sulfonic acid	8	RT	EtOH	10	45
11	Cellulose sulfonic acid	4	40	EtOH	10	68
12	Cellulose sulfonic acid	2	60	EtOH	10	96
13	Cellulose sulfonic acid	2	70	EtOH	10	96
14	Cellulose sulfonic acid	2	60	Toluene	10	25
15	Cellulose sulfonic acid	2	40	CH2Cl2	10	38
16	Cellulose sulfonic acid	2	60	MeOH	10	92

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Variation of the catalyst loading had a great effect on the catalytic activity (Table 3, entries 6–10). In the absence of the catalyst, the cyclization was accomplished only in 5% yield even after 48 hours. When the reaction was carried out using 2.0, 5.0, 10.0 and 13.0 mol%, both the rate of reaction and the chemical yields were evenly increased. However, the best result was observed using 10.0 mol% catalyst loading at 60 °C providing the product in 97% yield in 2 hours.

The reaction proceed at room temperature providing the product in 45% yield after 8 hours, while heating the reaction to 40 °C induced the cyclization furnishing the pyrazoline 5a in 68% yield. The best yield was observed when the reaction was performed at 60 °C in ethanol (Table 3 entries 10–13). The impact of different solvents on the reaction yield was also explored, dichloromethane as a chlorinated solvent and toluene as an aromatic solvent were utilized resulting in poor yields of the product. The best results were obtained in the presence of protic solvents and ethanol as an environmentally benign solvent was utilized to investigate the generality of the reaction (Table 3, entries 14–16).

The optimized reaction conditions were then applied to several different substrates bearing both electron-donating and withdrawing groups: dibenzylideneacetones with halogen atom substituents 3b–d (Table 4, entries 2–4) and methoxy substituent 3e (Table 4, entry 5) were well tolerated giving tri-substituted pyrazolines in high yields with an extra olefinic moiety for further manipulations. Finally, chalcone 3f in the presence of cellulose-SO₃H underwent cyclization to afford pyrazoline 5f in excellent yield (Table 4, entry 6). The plausible mechanism of this reaction is shown in Scheme 2. First, condensation of an α,β-unsaturated ketone with a hydrazine furnishes the corresponding hydrazone I which subsequently undergoes an electrocyclization process in the presence of Brønsted acid catalyst to afford the final pyrazoline adduct IV after isomerization.

Table 4 Reaction details of different α,β-unsaturated ketones 3 with phenyl hydrazine 4 in the presence of cellulose-SO₃H

Entry	Substrate	Product^a	Time^b (h)	Yield^c^,^d (%)
a Reaction conditions: substrates (1 mmol), catalyst (10 mol%), (10 mL EtOH), 60 °C.b Reaction progress monitored by TLC.c Isolated yield.d All products were characterized by comparison of their ^1H NMR spectra with those of authentic samples (see ESI).
1			2	96
2			2	98
3			2	96
4			2	93
5			3	92
6			5	91

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Scheme 2 Plausible mechanism for the Brønsted acid-catalyzed 6π electrocyclization of α,β-unsaturated hydrazones.

The catalyst reusability is an indispensable standard in heterogeneous catalysis fulfilling the green chemistry principles. The recyclability of the catalyst in the Nazarov cyclization was examined using the model reaction of dienone (1a) (1.00 mmol), in the presence of cellulose-SO₃H (0.4 g, 13 mol%) in ethanol (10 mL). After completion of the reaction, the catalyst was recovered by filtration, washed with EtOH (2 mL × 2) and dried in the oven at 60 °C. The recovered catalyst was weighed each time and then employed for further five additional consecutive runs under identical reaction conditions without any significant loss of catalytic activity (Fig. 2c).

Fig. 2 (a) FT-IR spectra of (i) cellulose-SO₃H and (ii) cellulose-SO₃H after three runs. (b) SEM image of the recovered catalyst (cellulose-SO₃H). (c) Recyclability of the catalyst (cellulose-SO₃H) for the Nazarov cyclization.

FT-IR analysis of the fresh and recovered catalyst (Fig. 2a) showed similar spectral patterns without any loss in intensity and the SEM analyses were also employed to investigate the changes that occurred in surface morphology of the recovered catalyst and a similar homogeneous fibrous morphology was revealed (Fig. 2b).

Conclusions

In conclusion, we have developed a high yielding, eco-friendly and simple procedure for the synthesis of five membered carbo- and heterocycles through cellulose sulfonic acid mediated electrocyclization processes. Cellulose-SO₃H was able to trigger the cyclization of “unactivated” dienones generating cyclopentenones in excellent yields under green reaction conditions. It was also easily recovered and reused up to five additional runs without notable loss in the catalytic activity. This biopolymer based solid acid was further employed for cyclization of α,β-unsaturated hydrazones generating pyrazolines in excellent yields. Carbohydrate based polymeric acids constitute excellent candidates for heterogeneous catalysis due to their biocompatibility, convenient manipulations and broad synthetic potentials. Their repeating structures result in spatial proximity and greater acidic density enabling cooperative effect among acid sites that give rise to enhanced acidic strength.⁴² Efforts to develop other carbohydrate based catalytic systems for applications in organic and polymer synthesis are underway in our laboratory.

Selected spectroscopic data for representative products

3,4-Bis(2-chlorophenyl)-2,5-dimethylcyclopent-2-enone (2b).
trans-3,4-Bis(2-chlorophenyl)-2,5-dimethylcyclopent-2-enone (2b′). White solid; 96% yield; mp: 109–110 °C; TLC R_f = 0.46 (8 : 2; n-hexane : EtOAc); ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 6.97–7.33 (m, 8H), 4.76 (q, 1H, J = 7.2), 2.49 (q, 1H, J = 7.2), 1.76 (s, 3H), 1.39 (d, 3H, J = 7.2); ¹³C NMR (100 MHz, CDCl₃): 210.5, 165.7, 139.7, 135.8, 134.6, 134.2, 134.1, 132.1, 130.2, 129.9, 129.7, 129.5, 129.0, 128.1, 126.7, 52.6, 49.0, 15.5, 9.9; IR (KBr, cm⁻¹): 2959, 2919, 2859, 1699, 1646, 1480, 1420, 1381, 1341, 1222, 1102, 1043, 837, 791, 751, 698, 645, 565, 453; Ms m/z (%): 331 (M⁺), 295, 267, 232, 202, 179, 152, 115, 75, 39. Anal calcd for C₁₉H₁₆Cl₂O: C, 68.89; H, 4.87; found C, 68.52; H, 5.38.
cis-3,4-Bis(2-chlorophenyl)-2,5-dimethylcyclopent-2-enone (2b′′). White solid; 96% yield; mp: 109–110 °C; TLC R_f = 0.46 (8 : 2; n-hexane : EtOAc); ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 6.97–7.33 (m, 8H), 5.36 (d, 1H, J = 5.7), 3.05 (dd, 1H, J = 7.5, 5.7), 0.76 (d, 3H, J = 7.5); ¹³C NMR (100 MHz, CDCl₃): 211.0, 164.8, 140.7, 134.9, 134.0, 134.6, 132.3, 129.9, 129.7, 129.1, 128.1, 127.1, 126.7, 126.5, 126.3; IR (KBr, cm⁻¹): 2959, 2919, 2859, 1699, 1646, 1480, 1420, 1381, 1341, 1341, 1222, 1102, 1043, 837, 791, 751, 698, 645, 565, 453; Ms m/z (%): 331 (M⁺), 295, 267, 232, 202, 179, 152, 115, 75, 39; anal calcd for C₁₉H₁₆Cl₂O: C, 68.89; H, 4.87; found C, 68.52; H, 5.38.

3,4-Bis(2,6-dichlorophenyl)-2,5-dimethylcyclopent-2-enone (2c).
trans-3,4-Bis(2,6-dichlorophenyl)-2,5-dimethylcyclopent-2-enone (2c′). White solid; 95% yield; mp: 130–131 °C; TLC R_f = 0.66 (9 : 1; n-hexane : EtOAc); ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 7.07–7.34 (m, 6H), 5.13 (d, 1H, J = 3.4), 3.01 (qd, 1H, J = 6.9, 3.4), 1.69 (s, 3H), 1.40 (d, 1H, J = 6.9); ¹³C NMR (100 MHz, CDCl₃): 211.5, 160.4, 136.9, 134.2, 134.0, 130.0, 129.9, 128.6, 128.2, 128.1, 128.0, 52.4, 45.2, 17.9, 9.0; IR (KBr, cm⁻¹): 2965, 2925, 2846, 1712, 1646, 1560, 1427, 1374, 1328, 1182, 1082, 956, 771; Ms m/z (%): 400 (M⁺), 372, 335, 300, 236, 215, 186, 149, 115, 63, 43. Anal calcd for C₁₉H₁₄Cl₄O: C, 57.03; H, 3.53; found C, 57.09; H, 3.48.
cis-3,4-Bis(2,6-dichlorophenyl)-2,5-dimethylcyclopent-2-enone (2c′′). White solid; 95% yield; mp: 130–131 °C; TLC R_f = 0.66 (9 : 1; n-hexane : EtOAc); ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 7.07–7.34 (m, 6H), 5.71 (d, 1H, J = 3.4), 3.01 (qd, 1H, J = 6.3, 3.4), 1.72 (s, 3H), 1.21 (d, 3H, J = 6.3); ¹³C NMR (100 MHz, CDCl₃): 209.6, 157.4, 142.4, 137.9, 137.2, 134.0, 131.1, 130.3, 128.7, 128.5, 128.0, 48.6, 45.1, 10.1, 9.3; IR (KBr, cm⁻¹): 2965, 2925, 2846, 1712, 1646, 1560, 1427, 1374, 1328, 1182, 1082, 956, 771; Ms m/z (%): 400 (M⁺), 372, 335, 300, 236, 215, 186, 149, 115, 63, 43 anal calcd for C₁₉H₁₄Cl₄O: C, 57.03; H, 3.53; found C, 57.09; H, 3.48.

3,4-Di(furan-2-yl)-2,5-dimethylcyclopent-2-enone (2d).
trans-3,4-Di(furan-2-yl)-2,5-dimethylcyclopent-2-enone (2d′). Orange solid; 96% yield; mp: 70–71 °C; TLC R_f = 0.45 (8 : 2; n-hexane : EtOAc); ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 6.10–7.55 (m, 8H), 3.95 (d, 1H, J = 3), 2.55 (qd, 1H, J = 7.5, 3), 2.16 (s, 3H), 1.30 (d, 3H, J = 7.5); ¹³C NMR (100 MHz, CDCl₃): 209.5, 154.7, 150.8, 150.5, 144.8, 141.6, 133.3, 114.7, 112.0, 110.3, 106.1, 47.4, 46.9, 29.6, 16.0, 9.9; IR (KBr, cm⁻¹): 3124, 2972, 2925, 2866, 1798, 1692, 1626, 1460, 1374, 1341, 1222, 1142, 1069, 1003, 983, 910, 817, 744, 698, 585; Ms m/z (%): 242 (M⁺), 199, 171, 128, 108, 77, 39. Anal calcd for C₁₅H₁₄O₃: C, 74.36; H, 5.82; found C, 74.28; H, 5.78.
cis-3,4-Di(furan-2-yl)-2,5-dimethylcyclopent-2-enone (2d′′). Orange solid; 96% yield; mp: 70–71 °C; TLC R_f = 0.46 (8 : 2; n-hexane : EtOAc); ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 6.04–7.56 (m, 8H), 4.60 (d, 1H, J = 7.2), 2.80 (qd, 1H, J = 7.5, 7.2), 2.18 (s, 3H), 0.9 (d, 3H, J = 7.5); ¹³C NMR (100 MHz, CDCl₃): 209.7, 153.3, 151.1, 150.4, 144.7, 141.6, 133.6, 114.3, 112.0, 110.2, 107.7, 44.7, 43.3, 29.7, 11.3, 9.9; IR (KBr, cm⁻¹): 3124, 2972, 2925, 2866, 1798, 1692, 1626, 1460, 1374, 1341, 1222, 1142, 1069, 1003, 983, 910, 817, 744, 698, 585; Ms m/z (%): 242 (M⁺), 199, 171, 128, 108, 77, 39. Anal calcd for C₁₅H₁₄O₃: C, 74.36; H, 5.82; found C, 74.28; H, 5.78.

2,5-Dimethyl-3,4-di(thiophen-2-yl)cyclopent-2-enone (2e).
trans-2,5-Dimethyl-3,4-di(thiophen-2-yl)cyclopent-2-enone (2e′). White solid; 92% yield; mp: 93–94 °C; TLC R_f = 0.50 (8 : 2; n-hexane : EtOAc); ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 6.80–7.51 (m, 8H), 4.26 (d, 1H, J = 2.4), 2.50 (qd, 1H, J = 7.5, 2.4), 2.17 (s, 3H), 1.35 (d, 3H, J = 7.5); ¹³C NMR (100 MHz, CDCl₃): 209.2, 157.4, 146.5, 138.0, 133.7, 130.2, 126.9, 124.7, 124.2, 51.7, 51.1, 16.3, 10.5; IR (KBr, cm⁻¹): 3098, 2965, 2919, 2866, 1745, 1692, 1606, 1414, 1381, 1334, 1208, 1049, 996, 857, 698; Ms m/z (%): 274 (M⁺), 207, 185, 150, 115, 75, 57, 39; anal calcd for C₁₅H₁₄OS₂: C, 65.66; H, 5.14; S, 23.37; found C, 65.52; H, 5.38; S, 23.32.
cis-2,5-Dimethyl-3,4-di(thiophen-2-yl)cyclopent-2-enone (2e′′). White solid; 92% yield; mp: 93–94 °C; TLC R_f = 0.50 (8 : 2; n-hexane : EtOAc); ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 6.79–7.25 (m, 8H), 4.86 (d, 1H, J = 7.2), 2.90 (qd, 1H, J = 7.5, 7.2), 2.20 (s, 3H), 0.90 (d, 3H, J = 7.5); ¹³C NMR (100 MHz, CDCl₃): 209.2, 157.5, 143.5, 138.5, 133.5, 129.7, 127.6, 127.0, 47.4, 45.9, 11.2, 10.4; IR (KBr, cm⁻¹): 3098, 2965, 2919, 2866, 1745, 1692, 1606, 1414, 1381, 1334, 1208, 1049, 996, 857, 698; Ms m/z (%): 274 (M⁺), 207, 185, 150, 115, 75, 57, 39; anal calcd for C₁₅H₁₄OS₂: C, 65.66; H, 5.14; S, 23.37; found C, 65.52; H, 5.38; S, 23.32.

3,4-Bis(2,6-dichlorophenyl)-2,5-diphenylcyclopent-2-enone (2f).
cis-3,4-Bis(2,6-dichlorophenyl)-2,5-diphenylcyclopent-2-enone (2f). White solid; 95% yield; mp: 103–104 °C; TLC R_f = 0.48 (8 : 2; n-hexane : EtOAc); ¹H NMR (300 MHz, CDCl₃): δ_H (ppm) 6.88–7.67 (m, 16H), 6.28 (d, 1H, J = 7.5), 4.61 (d, 1H, J = 7.5); ¹³C NMR (100 MHz, CDCl₃): 203.4, 156.8, 144.2, 131.1, 130.6, 130.1, 130.0, 128.9, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.5, 126.4, 53.2, 48.8; IR (KBr, cm⁻¹): 2434, 1713, 1557, 1430, 1337, 1225, 1167, 1055, 884, 782, 684, 606, 563; Ms m/z (%): 524 (M⁺), 489, 335, 276, 246, 212, 176, 150, 105, 77, 39; anal calcd for C₂₉H₁₈Cl₄O: C, 66.44; H, 3.46; found C, 66.42; H, 3.44.

Acknowledgements

We gratefully acknowledge funding from Shahid Beheshti university research council. The authors thank Dr Khosro Jadidi (Shahid Beheshti University) for providing us with some chemicals and Dr Saadi Samadi (University of Kurdistan) for his fruitful comments.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra19773b

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