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Article

A New Series of Tungstophosphoric Acid-Polymeric Matrix Catalysts: Application in the Green Synthesis of 2-Benzazepines and Analogous Rings

by
Edna X. Aguilera Palacios
1,
Valeria Palermo
1,
Angel G. Sathicq
1,
Luis R. Pizzio
1,* and
Gustavo P. Romanelli
1,2,*
1
Centro de Investigación y Desarrollo en Ciencias Aplicadas “Dr. Jorge J. Ronco” (CINDECA-CCT La Plata-CONICET), Universidad Nacional de La Plata, La Plata B1900AJK, Argentina
2
CISAV, Cátedra de Química Orgánica, Facultad de Ciencias Agrarias y Forestales, Universidad Nacional de La Plata, La Plata B1904AAN, Argentina
*
Authors to whom correspondence should be addressed.
Catalysts 2022, 12(10), 1155; https://doi.org/10.3390/catal12101155
Submission received: 8 September 2022 / Revised: 27 September 2022 / Accepted: 28 September 2022 / Published: 1 October 2022
(This article belongs to the Special Issue Feature Papers in Catalysis in Organic and Polymer Chemistry)
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Abstract

:
A new series of composite materials (PLMTPA) based on tungstophosphoric acid (TPA) included in a polymeric matrix of polyacrylamide (PLM), with a TPA:PLM ratio of 20/80, 40/60, and 60/40, were synthesized and well characterized by FT-IR, XRD, 31P MAS-NMR, TGA-DSC, and SEM-EDAX. Their acidic and textural properties were determined by potentiometric titration and nitrogen adsorption–desorption isotherms, respectively. Considering 31P MAS-NMR and FT-IR analyses, the main species present in the samples is the [PW12O40]3− anion that, according to XRD results, is highly dispersed in the polymeric matrix or appears as a noncrystalline phase. The thermogravimetric analysis revealed that PLMTPA materials did not undergo any remarkable chemical changes up to 200 °C. Additionally, the PLMTPA materials showed strong acid sites whose number increased with the increment of their TPA content. Finally, PLMTPA materials were used as efficient and recyclable noncorrosive catalysts for the synthesis of 2-benzazepines and related compounds. Good yields (55–88%) and high purity were achieved by a Pictet-Spengler variant reaction between N-aralkylsulfonamides and s-trioxane in soft reaction conditions: low toluene volume, at 70 °C, for 3 h. The described protocol results in a useful and environmentally friendly alternative with operative simplicity. The best catalyst in the optimized reaction conditions, PLMTPA60/40100, was reused six times without appreciable loss of activity.

Graphical Abstract

1. Introduction

The development of green chemistry has received great attention from researchers at the academic and industry levels, due to the need to preserve a global ecosystem [1,2]. In this context, the development of new materials that are environmentally friendly, robust, and have high-density active sites compared to the bulk catalyst has gained much interest in the field of suitable chemistry due to their catalytic properties in a large number of organic transformations [3,4,5].
In this regard, materials based on heteropolyacids, particularly those with Keggin structure, are considered greener catalysts than the corrosive liquid ones. They are safe, easy to separate, generate a low amount of waste, and present stability and high acidity. Recently, our research group reported the use of materials based on Keggin heteropolyacids in heterocycle synthesis [6], green selective oxidation [7], and biomass valorization [8].
The drawback of heteropolyacids is their low surface area (<10 m2/g), which limits their use in many transformations. This disadvantage can be overcome by dispersing the heteropolyacids on a solid support with high surface area. Thus, the search for new materials for dispersing heteropolyacids is a pressing need [9].
Polymeric matrices are a new type of support that can be used when catalysts are employed in reactions carried out at temperatures below 200 °C, due to their relatively low thermal stability. Among them, polyvinyl alcohol–polyethylenglycol and poly(acrylic acid-co-acrylamide) polymers were used by our group for the efficient immobilization of tungstophosphoric acid (H3PW12O40) [10,11,12], its aluminum or copper salt [11,13], and polyoxotungstovanadates, such as [PVW11O40]4−, [PV2W10O40]5−, [SiVW11O40]5−, and [SiV2W10O40]6−) [14,15]. The hybrid materials were used as catalysts in organic reactions (anisole acylation and the selective oxidation of sulfide to sulfones) performed at low temperatures.
Furthermore, benzazepine derivatives are promising bioactive compounds that are generally synthesized in multiple steps, leading to the generation of stoichiometric amounts of waste [16]. They have relevant biological properties, including anxiolytic, dopaminergic, anthelmintic, antimicrobial, antitumor, anti-HIV, bronchodilator, antiarrhythmic activity, among others, and are used in Parkinson’s disease treatment [17,18,19,20,21,22,23,24]. These compounds are also potentially good candidates for new drug therapies to treat skin and wounds [25]. The importance of these compounds is reflected in a very recent paper by Katalin Barta et al. In this report, the authors revealed the possibility of obtaining the benzo[c]azepine skeleton from residual biomass to be used as a platform molecule for obtaining potential bioactive molecules [26].
There are several strategies for benzo[c]azepine and analogous ring synthesis. The most suitable method to prepare these heterocycles includes the formation of the imino intermediate from arylalkylamine and a carbonyl compound, followed by an intramolecular aromatic electrophilic substitution for generating the benzazepine ring [27,28,29].
It is important to highlight that certain groups attached to the nitrogen atom of N-arylalkylamine increase the yields of the final intramolecular cyclization (an acyl or sulfonyl group notably increases the reactivity) [30].
Recently, our research group reported a suitable procedure for preparing N-sulfonyl-1,2,3,4-tetrahydroisoquinolines using Wells-Dawson [31] and Preyssler heteropolyacids [32] supported on silica.
In continuation of our efforts toward the development of green synthetic methodologies and a new material based on heteropolyacids, herein we report the synthesis and characterization of very efficient, suitable, and recyclable materials based on tungstophosphoric acid included in a polymeric matrix of polyacrylamide and their use as heterogeneous catalysts for the synthesis of benzo[c]azepines and analogous rings. Scheme 1 shows the synthesis of one N-aralkylsulfonyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine using this catalytic methodology.

2. Results and Discussion

2.1. Catalyst Characterization

The polymeric matrix has -CONH2 groups that can be protonated in the presence of a strong acid such as tungstophosphoric acid, allowing the electrostatic interaction of these groups and the anions [H3−xPW12O40]x−(where 1 < x ≤ 3). It has been reported that H+ transfer from [H3PW12O40] to the amine group, resulting in an electrostatic bond between -NH3+ and [H3−xPW12O40]x−, is responsible for the efficient immobilization of the heteropolyanion [33,34].
The absence of W in the water solution C (obtained from the chloride elimination step) shows that TPA leaching is negligible due to the aforementioned strong interaction.
According to SEM micrographs (Figure 1), PLMTPAXX/YY samples present a sponge-like structure formed by a network of cross-linked channels. The tungsten microanalysis performed by EDAX showed that TPA content along the diameter of the spheres is almost uniform, with a slight increase on their surface.
The SBET values of the PLMTPA60/40T100, PLMTPA40/60T100, and PLMTPA20/80T100 materials are lower than 10 m2/g (6, 4 and 3 m2/g, respectively) and in the same range as those of the bulk TPA and PLM (9 and 2 m2/g, respectively).
TPA FT-IR spectrum (Figure 2) shows the bands assigned to the stretching vibrations P-Oa (1081 cm−1), W-Od (982 cm−1), W-Oc-W (888 cm−1), W-Oc-W (793 cm−1), and to the bending vibration Oa-P-Oa (595 cm−1) [35] (see the subscript meaning in supplementary materials).
The bands assigned to the stretching vibrations W-Oc-W, W-Ob-W, and P-Oa in the spectrum of PLMTPA60/40T100, PLMTPA40/60T100, and PLMTPA20/80T100 samples overlap the characteristic bands of PLM (Figure 2). Their intensity increases with the increment of the sample TPA content, and it confirms the presence of [PW12O40]3− anion as the main species. The FT-IR spectra of samples treated at 200 and 300 °C display similar characteristics. However, in the samples calcined at a higher temperature, the relative intensity of the TPA main bands slightly increases due to PLM chemical transformation and partial decomposition (Figure S2).
The 31P MAS-NMR spectra of PLMTPA20/80T100, PLMTPA40/60T100 and PLMTPA60/40T100 samples (Figure 3) display a narrow band with a maximum at around −15.0 ppm, attributed to the [PW12O40]3− anion. The PLMTPA20/80 spectrum also shows a wider and less intense band at −12.1 ppm, assigned to the [P2W21O71]6− dimeric species [36,37].
Based on the FT-IR and 31P MAS-NMR results, we can conclude that the [PW12O40]3− anion is the main species in the PLMTPA samples. However, the anion was partially transformed into [P2W21O71]6− dimeric species during the synthesis due to the limited stability range of the [PW12O40]3− anion in solution [38]. No significant changes in the 31P MAS-NMR spectra of the samples treated at 200 and 300 °C were found. These results agree with reports showing that an appreciable transformation of [PW12O40]3− into [P2W21O71]6− takes place at 400 °C or higher temperatures [39].
The DSC diagram of dried PLM (Figure 4) exhibits three endothermic peaks at 199, 300 and 400 °C, which are assigned to the glass transition (Tg) and polymer decomposition [40,41]. Above Tg and up to 350 °C, the intra- and intermolecular imidization of the amido groups (with the release of NH3) and the formation of nitrile groups from the amido group dehydration take place. At temperatures above 350 °C, imide decomposition (with the release of CO2 and H2O) and the rupture of the polymeric chain (with the formation of long hydrocarbon chains) occur. According to the TGA analysis, the PLM degradation takes place in two steps between 250 and 350 °C and 350 and 460 °C. The weight loss associated with these steps was 22% and 64%, respectively. TGA diagrams of PLMTPA20/80T100, PLMTPA40/60T100 and PLMTPA60/40T100 samples exhibit the two aforementioned degradation steps. The weight loss ascribed to these steps decreases in parallel with the increment of TPA content in the materials (see Table S1 in supplementary materials).
The DSC diagrams of the PLMTPA20/80T100 and PLMTPA40/60T100 samples (Figure 4) present the three endothermic peaks mentioned above at slightly lower temperatures. In the case of the PLMTPA40/60T100 material, the peak assigned to the glass transition is barely visible. For the PLMTPA60/40T100 samples, the glass transition peak is not present, and the other two endothermic peaks appear at lower temperatures (279 and 385 °C). These results show that PLMTPAXX/YYT100 materials do not undergo any remarkable chemical changes up to 200 °C.
The XRD diagrams of the PLMTPA20/80T100, PLMTPA40/60T100 and PLMTPA60/40T100 samples (Figure 5) show a new set of broad- and low-intensity peaks overlapping the XRD pattern of bulk PLM; however, they resemble neither those of the H3PW12O40 (JCPDS No. 50-0657) nor those of its more common hydrates (H3PW12O40·6H2O and H3PW12O40·23H2O) [42]. The intensity of these peaks slightly increases as the TPA content rises. These results suggest that most of the TPA is present in the polymeric matrix as a noncrystalline phase. On the other hand, the small TPA crystals seem to be strongly immobilized in the PLM matrix, since they were not removed during the washing with water (three times for 24 h each) performed to eliminate the chloride. The XRD diagrams of samples treated at higher temperatures present similar characteristics.
The acidity properties of the PLMTPAXX/YY materials, estimated from the potentiometric titration with n-butylamine curves (Figure 6), are listed in Table 1. According to the potentiometric results, all the materials exhibit Ei values higher than 100 mV [43], assigned to the presence of very strong acid sites (see the classification scale in supplementary materials).
The acid strength of PLMTPA20/80T100 (Ei = 194 mV), PLMTPA40/60T100 (Ei = 182 mV), and PLMTPA60/40T100 (Ei = 191 mV) samples is higher than that of PLM (Ei = −44 mV) but lower than that of bulk TPA (Ei = 620 mV) [44]. The lower acid strength of the PLMTPAXX/YY materials compared to bulk TPA could be due to the fact that the protons in TPA are present as H+(H2O)2 species (hydrated protons), whereas in the PLMTPA samples they interact with the nitrogen of -CONH2 groups.
The number of acid sites (NS) estimated as the area under the curve increases in the following order: PLMTPA20/80T100 > PLMTPA40/60T100 > PLMTPA60/40T100 (84, 146, and 201 meq n-butylamine/g, respectively) in parallel with the increment of TPA content. On the other hand, the thermal treatment of the samples at higher temperatures decreased both Ei and Ns (Figure S3), because of the structural and chemical modification of the PLM matrix.

2.2. Catalytic Test for N-(3,4-Dichlorobenzylsulfonyl)-2,3,4,5-Tetrahydro-1H-Benzo[c]azepine Synthesis

The most suitable catalyst was identified using the test reaction between N-phenylpropyl-3,4-dichlorobenzylsulfonamide and s-trioxane as substrate (see Scheme 1), with toluene as solvent, at 70 °C for 3 h to obtain N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine.
First, we performed a blank experiment without the catalyst, and no reaction was observed (Table 1, entry 1). Likewise, no reaction was observed when the support (PLM) was used, under the same conditions (Table 1, entry 2). Subsequently, the PLMTPA materials were tested, showing very good conversion and selectivity of the desired product (Table 1, entries 3–5). In these three experiments, very good product yields were obtained for PLMTPA20/80T100, PLMTPA40/60T100 and PLMTPA60/40T100 samples (48%, 62% and 83%, respectively), indicating the need to use a catalyst with acidic properties to produce N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine. According to the acidity measurements of the PLMTPA samples obtained by potentiometric titration, the Ns in the catalysts increases as follows: PLMTPA20/80T100 < PLMTPA40/60T100 < PLMTPA60/40T100. The N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yield increases in the same way, suggesting that the acidity strongly affects the catalytic activity of the PLMTPA catalysts. The yields obtained for the samples calcined at 200 and 300 °C (Table 1, entries 6 and 7) confirm that the drop in Ns and acid strength leads to a decrease in N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine production. On the other hand, the yield obtained using bulk TPA in the same reaction conditions was lower (41%) than those achieved using the PLMTPA20/80T100, PLMTPA40/60T100, and PLMTPA60/40T100 catalysts. Consequently, the TPA inclusion in the polymer matrix (mainly present as a noncrystalline phase) increases the N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields and facilitates the catalyst recovery (by simple centrifugation and filtration) from the reaction medium for its subsequent reuse. On the contrary, the recovery of bulk TPA was more difficult, because it must be washed several times with the reaction solvent to eliminate product traces covering its surface.
To evaluate the influence of the solvent nature, the reaction was conducted using benzene, chloroform, dichloromethane, and hexane instead of toluene (Table 2). All solvents were selected due to TPA insolubility in them.
Similar results were obtained using aromatic hydrocarbons such as toluene and benzene (Table 2, entries 1 and 2: 83% and 80%, respectively). The use of chlorinated solvents gives lower yields (Table 2, entries 3 and 4: 68% and 52%, respectively). Finally, hexane gives a poor yield (Table 2, entry 5: 35%) due to the very low solubility of the substrates in the reaction medium. Therefore, toluene was chosen as solvent for the next experiments because, although benzene gives comparable results, it is classified as a carcinogen, which increases the risk of cancer and other illnesses.
To evaluate the influence of reaction temperature, five temperatures (25, 50, 70, 90, and 110 °C) were checked in identical reaction conditions (see Table 3). No product formation was observed at room temperature (25 °C) (Table 3, entry 1). A temperature increase to 70 °C leads to higher N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-2-benzo[c]azepine yields. The maximum yield for a reaction time of 3 h at 70 °C is 83% (Table 3, entry 3). The catalytic performance in the reaction drops considerably when raising the temperature to 90 and 100 °C (Table 3, entries 4 and 5: 69% and 51%, respectively). In these cases, the formation of several secondary products, which were detected by TLC (and were not identified), was observed. Based on these results, 70 °C was the reaction temperature chosen for the next experiments.
Table 4 shows the results obtained under the already optimized reaction conditions (toluene as solvent and 70 °C temperature) as a function of time (0.5, 2, 3, 4, and 6 h). The reaction yields increased with time up to 3 h (Table 4, entry 3) and then remained at a constant value.
Table 5 displays the catalyst amount effect on the yield of N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine. The reaction yields increased from 69% to 83% when the catalyst amount increased from 0.5% to 1% (Table 5, entries 1 and 2). There were no substantial changes by raising the catalyst amount up to 2% (Table 5, entries 3 and 4).
The PLMTPA60/40100 reuse was evaluated under optimized reaction conditions: substrate, 0.5 mmol; s-trioxane, 1.5 mmol; toluene, 2 mL; catalyst, 1% mmol; temperature, 70 °C, and reaction time, 3 h. After each run, the catalyst was filtered, washed with three portions of toluene, dried under vacuum at 25 °C for 24 h, and reused. Each reuse test is presented in Table 6, showing that the catalyst can be reused for six cycles without appreciable loss of its catalytic activity.
The possible TPA leaching from the catalyst into the reaction media was evaluated as follows: a sample of PLMTPA60/40100 catalyst (the one with the highest TPA content) was refluxed in toluene (3 mL) for 6 h, filtered in vacuum, and dried to constant weight. The activity of the PLMTPA60/40100 catalyst was evaluated, being similar to that evaluated with the fresh catalyst (82%, 70 °C, 3 h). The refluxed toluene was used as solvent for attempting the N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine synthesis without adding the catalyst. After 6 h at 70 °C, no significant amounts of the product were detected, and the substrate was recovered quantitatively from the reaction media.
Finally, another experiment consisted of withdrawing the catalyst after 1 h of reaction; the reaction was followed for two more hours, and the reaction yields were evaluated. The reaction yields at 1 and 3 h were practically the same (38% and 40%, respectively), indicating that the synthesis reaction takes place in a heterogeneous phase.
Using the best reaction conditions found for N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine synthesis (N-aralkylsulfonamide, 0.5 mmol; s-trioxane, 1.5 mmol; toluene, 2 mL; catalyst, PLMTPA60/40100, 1% mmol; and 70 °C, 3 h), various benzo[c]azepines, isoquinolines, and one benzo[c]azocine were prepared. The methodology is not appropriate to prepare analogous rings of five, eight, and nine members, because of the low yield. However, it is suitable for the preparation of heterocycles with six and seven members (Table 7).
Table 8 shows comparative results for the N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine synthesis using different acid catalysts. Better results were obtained using heterogeneous catalysts based on HPAs (Table 8, entries 3–5), probably due to the milder conditions than the methanesulphonic acid/trifluoracetic acid and methanesulphonic/acetic anhydride media (Table 8, entries 1 and 2).

2.3. Mechanism of 2,3,4,5-Tetrahydro-1H-benzo[c]azepine and Analogous Ring Synthesis

A plausible mechanism for the synthesis of 2,3,4,5-tetrahydro-1H-benzo[c]azepines and analogous rings is described. This reaction involves the formation of a benzazepine or a homolog in the nitrogen ring from a sulfonamide and formaldehyde formed in situ from s-trioxane. The reaction is catalyzed by a strong acid. The proposed mechanism corresponds to the reaction in which the catalyst is a supported HPA (Scheme 2).
Initially, the catalyst coordinates with an s-trioxane molecule forming the adduct (1), which undergoes nucleophilic attack by the sulfonamide, simultaneously with the protonation of s-trioxane, resulting in the alkylation of the N atom by a hydroxymethyl and the formation of an ammonium ion (2).
At the acidic catalytic site, the conjugate base of the catalyst is generated momentarily, which stabilizes the ion by forming a bifurcated hydrogen bridge to both acidic hydrogens. A transfer of a proton protonates the catalyst again, which is coordinated to the hydroxymethylsulfonamide (3). A new proton transfer forms oxonium (4) from (3). Oxonium (4) is again coordinated with the conjugate base of the catalyst and undergoes an intramolecular electrophilic aromatic substitution while removing a molecule of water. Intermediate (5) is finally deprotonated, forming benzo[c]azepine (or analogous ring) (6) and regenerating the catalyst.
Since Barry Trost introduced the atom economy concept in 1991 [45] and Paul Anastas and John Warner defined the 12 principles of green chemistry [46], several groups, including ours, have started to consider the best ways to adopt this working approach. One way of verifying how close the synthesis method used is to an ideal process, from the green chemistry point of view, is using some of the green parameters defined by John Andraos and coworkers in several publications [47,48,49] and representing them in a polygon graphic. In our case, we decided to represent five of these parameters, atom economy (AE), reaction yield (RY), stoichiometry factor (SF), material recovery parameter (MRP), and reaction mass efficiency (RME), in a radial pentagon (Figure 7a,b). For comparative purposes, we studied the green parameters on the same reaction with (Figure 7b) and without (Figure 7a) solvent and catalyst recovery. We noted that the change was in the MRP parameter, which increased approximately ten times when we recovered the solvent and catalyst.

3. Materials and Methods

3.1. Catalyst Preparation

First, a solution containing 7.5 g of PLM (polyacrylamide, Aldrich, Darmastadt, Germany, MW = 1.5 × 105), 180 mL of formamide (Sigma, Kawasaki, Kanagawa, Japan), and 7.5 mL of distilled water was prepared (solution A). Then, an appropriate amount of TPA (H3PW12O40·23H2O, Fluka, St Gallen, Switzerland dissolved in 12.5 mL of distilled water (solution B) was added to the former solution. The mixture (solution C) was stirred to homogeneity. The solution was slowly dropped into concentrated hydrochloric acid to form spherical catalyst particles. The spheres (mean diameter ~3 mm, see supplementary materials, Figure S1) were separated by filtration, washed (three times for 24 h each) with distilled water (until the complete elimination of Cl−), and then dried overnight at 75 °C. The amounts of TPA used were fixed to obtain a TPA:PLM ratio of 20/80, 40/60, and 60/40, respectively. Therefore, the catalysts were labeled PLMTPA20/80, PLMTPA40/60, and PLMTPA60/40. The materials were calcined at 100, 200, and 300 °C for 24 h under air atmosphere. The obtained solids were named PLMTPAXX/YY100, PLMTPAXX/YY200, and PLMTPAXX/YY300, respectively. The TPA content in the PLMTPAXX/YY100 materials was estimated as the difference between the W amount in the tungstophosphoric acid water solution (solution A) and the amount of W that remained in the beaker containing the reaction mixture (solution B). Furthermore, the water samples collected from the chloride elimination step (solution C) were analyzed to evaluate the possible TPA leaching (see supplementary materials).

3.2. Sample Characterization

The nitrogen adsorption/desorption measurements were carried out at liquid nitrogen temperature (−196 °C) using Micromeritics ASAP 2020 equipment (Norcross, GA, USA). From the obtained data, the specific surface area (SBET) was determined using the Brunauer-Emmett-Teller model.
The morphology and structural properties of the PLMTPAXX/YY samples were characterized by scanning electron microscopy (SEM, with Philips 505 equipment, Eindhoven, Netherlands), energy-dispersive X-ray analysis (EDAX), and X-ray diffraction analysis (XRD, employing Philips PW-1732 equipment, Eindhoven, Netherlands). See more details in the supplementary materials.
The species present in the materials were evaluated by Fourier transform infrared spectroscopy (FT-IR, using Bruker IFS 66 equipment, Billerica, MA, USA) and 31P nuclear magnetic resonance (P MAS-NMR, using Bruker MSL-300 equipment, Billerica, MA, USA); more details about both techniques can be found in the supplementary materials.
The acid strength and the number of acid sites were estimated from the n-butylamine potentiometric titration results (for more details about the technique, see supplementary materials).
TGA and DSC were carried out with Shimadzu DT 50 equipment, in an aluminum plate under nitrogen flow. The heating rate was 10 °C/min from 20 to 600 °C.

3.3. Catalytic Test for N-(3,4-Dichlorobenzylsulfonyl)-2,3,4,5-Tetrahydro-1H-Benzo[c]azepine Synthesis

Chemicals were purchased from Merck (Darmstadt, Germany, Aldrich, and Fluka and used after purification by standard procedures. The starting materials were prepared by procedures described in the literature. Most of the aralkylamines were obtained from the corresponding nitriles using NaBH4-SnCl4 [50]. The sulfonyl chlorides and the sodium sulfonates needed for their preparation were obtained by general methods [30]. The N-aralkylsulfonamides were prepared following Orazi et al.’s methodology [30].
The reactions were monitored by thin-layer chromatography silica gel plates coated with fluorescent indicator F254. All of the yields were calculated from pure products. Melting points were determined in sealed capillary tubes and are uncorrected. The 1H NMR and 13C NMR spectra were recorded on a Bruker 400 MHz instrument as CDCl3 solutions. All of the products were identified by a comparison of physical reported data (supplementary materials).
The PLMTPAXX/YY materials were ground (particle size, ~0.1 mm) and dried at room temperature in vacuum for 24 h. The test was performed in a reaction test tube, equipped with a reflux condenser, and immersed in an oil bath. In a typical experiment, N-phenylpropyl-3,4-dichlorobenzylsulfonamide (0.5 mmol), s-trioxane (1.5 mmol), and the appropriate amount of catalyst in toluene (2 mL) were heated to 70 °C with magnetic stirring (600 rpm) for 3 h. The catalyst was filtered and washed with toluene (3 × 0.5 mL). The organic solution was dried over anhydrous magnesium sulfate. The desiccant was filtered, and the solution was concentrated. The benzazepines (and related compounds) were recrystallized from acetone or ethyl acetate to afford the corresponding pure products.

3.4. Catalyst Reuse

The stability of PLMTPA60/40100, the catalyst with the best performance, was evaluated in six consecutive runs, under identical reaction conditions. After each run, the catalyst was filtered from the reaction medium, washed with toluene, dried under vacuum, and then reused.

4. Conclusions

In the present work, we successfully modified the surface of the polymeric matrix by tungstophosphoric acid heterogeneous catalysts and characterized them by nitrogen adsorption–desorption isotherms, FT-IR, 31P MAS-NMR, DTA-TGA, SEM, XRD, and potentiometric titration. The catalysts were then used for the synthesis of N-(sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepines and analogous rings. This methodology requires a short reaction time of 3 h and a temperature of 70 °C to obtain very good yields of benzo[c]azepines and analogous rings. An 83% yield was achieved in toluene and 1% PLMW60/40100, the catalyst with the greater number of acid sites. The recyclability and reuse of the PLMW60/40100 catalyst were established for up to six successive runs with no dramatic loss in the reaction profile.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal12101155/s1, include leaching analysis; characterization technique details; digital photograph; complementary FT-IR, potentiometric curves, and TGA of the catalysts; and the 1H and 13C NMR spectra and melting points of synthesized benzazepines and related compounds. Figure S1: PLMTPA60/40100 catalyst spheres; Figure S2: FT-IR spectrum of PLMTPA60/40 treated at 100 (PLMTPA40/60T100), 200 (PLMTPA40/60T200), and 300 °C (PLMTPA40/60T300); Figure S3: Potentiometric titration curves of PLMTPA60/40T100, PLMTPA60/40T200, and PLMTPA60/40T300 samples; Table S1: Weight loss of the polymer and catalysts obtained by TGA.

Author Contributions

Conceptualization, L.R.P. and G.P.R.; methodology, E.X.A.P., A.G.S., L.R.P. and G.P.R.; formal analysis, E.X.A.P., V.P., A.G.S., L.R.P. and G.P.R.; investigation, E.X.A.P. and V.P.; data curation, E.X.A.P., V.P., A.G.S. and L.R.P.; writing—review and editing, E.X.A.P., V.P., L.R.P. and G.P.R.; supervision, A.G.S., L.R.P. and G.P.R.; project administration, L.R.P. and G.P.R.; funding acquisition, L.R.P. and G.P.R.. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by UNLP (A349, X879) and CONICET (PIP0111, PIP1492).

Data Availability Statement

Not applicable.

Acknowledgments

The authors thank the microscopy and analytical departments of CINDECA for the experimental measurement.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 12 01155 sch001 550
Scheme 1. Catalytic test for N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine synthesis.
Scheme 1. Catalytic test for N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine synthesis.
Catalysts 12 01155 sch001
Catalysts 12 01155 g001 550
Figure 1. SEM micrograph (with (a) 100× and (b) 10× magnification) and (c) EDAX (W Lα1 line 8.396 KeV) mapping of the PLMTPA60/40T100 sample.
Figure 1. SEM micrograph (with (a) 100× and (b) 10× magnification) and (c) EDAX (W Lα1 line 8.396 KeV) mapping of the PLMTPA60/40T100 sample.
Catalysts 12 01155 g001
Catalysts 12 01155 g002 550
Figure 2. FT-IR spectra of PLMTPA60/40T100, PLMTPA40/60T100, and PLMTPA20/80T100 samples, bulk TPA and PLM.
Figure 2. FT-IR spectra of PLMTPA60/40T100, PLMTPA40/60T100, and PLMTPA20/80T100 samples, bulk TPA and PLM.
Catalysts 12 01155 g002
Catalysts 12 01155 g003 550
Figure 3. 31P MAS-NMR spectra of PLMTPA20/80T100, PLMTPA40/60T100 and PLMTPA60/40T100 samples.
Figure 3. 31P MAS-NMR spectra of PLMTPA20/80T100, PLMTPA40/60T100 and PLMTPA60/40T100 samples.
Catalysts 12 01155 g003
Catalysts 12 01155 g004 550
Figure 4. DSC diagrams of PLMTPA20/80T100, PLMTPA40/60T100 and PLMTPA60/40T100 samples.
Figure 4. DSC diagrams of PLMTPA20/80T100, PLMTPA40/60T100 and PLMTPA60/40T100 samples.
Catalysts 12 01155 g004
Catalysts 12 01155 g005 550
Figure 5. XRD patterns of H3PW12O40·23H2O (JCPDS No 50-0655), H3PW12O40·6H2O (JCPDS No. 50-0304), PLMTPA60/40T100, PLMTPA40/60T100, PLMTPA20/80T100, and PLM samples.
Figure 5. XRD patterns of H3PW12O40·23H2O (JCPDS No 50-0655), H3PW12O40·6H2O (JCPDS No. 50-0304), PLMTPA60/40T100, PLMTPA40/60T100, PLMTPA20/80T100, and PLM samples.
Catalysts 12 01155 g005
Catalysts 12 01155 g006 550
Figure 6. Potentiometric titration curves of PLMTPA20/80T100, PLMTPA40/60T100 and PLMTPA60/40T100 samples.
Figure 6. Potentiometric titration curves of PLMTPA20/80T100, PLMTPA40/60T100 and PLMTPA60/40T100 samples.
Catalysts 12 01155 g006
Catalysts 12 01155 sch002 550
Scheme 2. Plausible mechanism for benzo[c]azepine and analogous ring synthesis.
Scheme 2. Plausible mechanism for benzo[c]azepine and analogous ring synthesis.
Catalysts 12 01155 sch002
Catalysts 12 01155 g007 550
Figure 7. Radial pentagon for N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine synthesis (a) without solvent and catalyst recovery and (b) with solvent and catalyst recovery.
Figure 7. Radial pentagon for N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine synthesis (a) without solvent and catalyst recovery and (b) with solvent and catalyst recovery.
Catalysts 12 01155 g007
Table
Table 1. Effect of different catalysts on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields (%).
Table 1. Effect of different catalysts on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields (%).
EntryCatalystEi
(mV)		Ns aYields
(%) b
1None---
2PLM44--
3PLMTPA20/801001948448
4PLMTPA40/6010018214662
5PLMTPA60/4010019120183
6PLMTPA60/4020018015862
7PLMTPA60/4030090779
Reaction conditions: N-phenylpropyl-3,4-dichlorobenzylsulfonamide, 0.5 mmol; s-trioxane, 1.5 mmol; toluene, 2 mL; catalyst, 1% mmol; 70 °C; 3 h; stirring. a meq/g. b Pure product.
Table
Table 2. Solvent effect on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields (%).
Table 2. Solvent effect on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields (%).
EntrySolventYields (%) a
1Toluene83
2Benzene80
3Chloroform68
4Dichlorometane b52
5Hexane b35 c
Reaction conditions: N-phenylpropyl-3,4-dichlorobenzylsulfonamide, 0.5 mmol; s-trioxane, 1.5 mmol; solvent, 2 mL; catalyst PLMTPA60/40100, 1% mmol; 70 °C; 3 h; stirring. a Pure product. b The reaction was performed at 40 °C. c The substrate is partially soluble in this reaction solvent.
Table
Table 3. Temperature effect on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields (%).
Table 3. Temperature effect on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields (%).
EntryTemperature (°C)Yields (%) a
125-
25039
37083
49069
511051
Reaction conditions: N-phenylpropyl-3,4-dichlorobenzylsulfonamide, 0.5 mmol; s-trioxane, 1.5 mmol; toluene, 2 mL; catalyst PLMTPA60/40100, 1% mmol; 3 h; stirring. a Pure product.
Table
Table 4. Reaction time effect on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields (%).
Table 4. Reaction time effect on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields (%).
EntryTime (h)Yields (%) a
10.517
2138
3277
4383
5482
6680
Reaction conditions: N-phenylpropyl-3,4-dichlorobenzylsulfonamide, 0.5 mmol; s-trioxane, 1.5 mmol; toluene, 2 mL; catalyst = PLMTPA60/40100, 1% mmol; 70 °C; stirring. a Pure product.
Table
Table 5. Catalyst amount effect on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields (%).
Table 5. Catalyst amount effect on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields (%).
EntryCatalyst Amount (%)Yields (%) a
10.569
2183
31.583
4282
Reaction conditions: N-phenylpropyl-3,4-dichlorobenzylsulfonamide, 0.5 mmol; s-trioxane, 1.5 mmol; toluene, 2 mL; catalyst PLMTPA60/40100; 70 °C; 3 h; stirring. a Pure product.
Table
Table 6. Catalyst reuse effect on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields (%).
Table 6. Catalyst reuse effect on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine yields (%).
EntryCycleYields (%) a
1183
2281
3383
4482
5577
6679
Reaction conditions: N-phenylpropyl-3,4-dichlorobenzylsulfonamide, 0.5 mmol; s-trioxane, 1.5 mmol; toluene, 2 mL; catalyst PLMTPA60/40100, 1% mmol; 70 °C; 3 h stirring. a Pure product.
Table
Table 7. Substrate effect on N-(aralkylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine and analogous ring yields (%).
Table 7. Substrate effect on N-(aralkylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine and analogous ring yields (%).
EntrySubstrateCycle SizeProductYields (%) a
1Catalysts 12 01155 i0016Catalysts 12 01155 i00288
2Catalysts 12 01155 i0037Catalysts 12 01155 i00483
3Catalysts 12 01155 i0056Catalysts 12 01155 i00620
4Catalysts 12 01155 i0077Catalysts 12 01155 i008-
5Catalysts 12 01155 i0097Catalysts 12 01155 i01080
6Catalysts 12 01155 i0116Catalysts 12 01155 i01255
7Catalysts 12 01155 i0136Catalysts 12 01155 i01488
Reaction conditions: N-aralkylsulfonamide, 0.5 mmol; s-trioxane, 1.5 mmol; toluene, 2 mL; catalyst PLMTPA60/40100, 1% mmol; 70 °C; 3 h; stirring. a Pure product.
Table
Table 8. Use of different catalysts on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine synthesis.
Table 8. Use of different catalysts on N-(3,4-dichlorobenzylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine synthesis.
EntryCatalyst Yields (%)Reference
1Methanesulphonic acid/ trifluoroacetic acid68[30]
2Methanesulphonic acid/ acetic anhydride70[30]
3H6P2W18O62/SiO284[31]
4H14[NaP5W30O110]/SiO281[32]
5PLMTPA60/4010083This work
Data from cited references.
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Aguilera Palacios, E.X.; Palermo, V.; Sathicq, A.G.; Pizzio, L.R.; Romanelli, G.P. A New Series of Tungstophosphoric Acid-Polymeric Matrix Catalysts: Application in the Green Synthesis of 2-Benzazepines and Analogous Rings. Catalysts 2022, 12, 1155. https://doi.org/10.3390/catal12101155

AMA Style

Aguilera Palacios EX, Palermo V, Sathicq AG, Pizzio LR, Romanelli GP. A New Series of Tungstophosphoric Acid-Polymeric Matrix Catalysts: Application in the Green Synthesis of 2-Benzazepines and Analogous Rings. Catalysts. 2022; 12(10):1155. https://doi.org/10.3390/catal12101155

Chicago/Turabian Style

Aguilera Palacios, Edna X., Valeria Palermo, Angel G. Sathicq, Luis R. Pizzio, and Gustavo P. Romanelli. 2022. "A New Series of Tungstophosphoric Acid-Polymeric Matrix Catalysts: Application in the Green Synthesis of 2-Benzazepines and Analogous Rings" Catalysts 12, no. 10: 1155. https://doi.org/10.3390/catal12101155

APA Style

Aguilera Palacios, E. X., Palermo, V., Sathicq, A. G., Pizzio, L. R., & Romanelli, G. P. (2022). A New Series of Tungstophosphoric Acid-Polymeric Matrix Catalysts: Application in the Green Synthesis of 2-Benzazepines and Analogous Rings. Catalysts, 12(10), 1155. https://doi.org/10.3390/catal12101155

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