Palladium Nanoparticles Supported on Smopex-234 ® as Valuable Catalysts for the Synthesis of Heterocycles

: Supported catalysts are important tools for developing green-economy-based processes. Palladium nanoparticles (NPs) that are immobilized on two ﬁbers developed as metal scavengers (i.e., Smopex ® -234 and Smopex ® -111, 1% w/w ) have been prepared and tested in copper-free cyclocarbonylative Sonogashira reactions. Their catalytic activity has been compared with that of a homogeneous catalyst (i.e., PdCl 2 (PPh 3 ) 2 ). Pd/Smopex ® -234 showed high activity and selectivity in the synthesis of functionalized heterocycles, such as phthalans and isochromans, even when working with a very low amount of palladium (0.2–0.5 mol%). The extension of Pd/Smopex ® -234 promoted cyclocarbonylative reactions to propargyl and homopropargyl amides afforded the corresponding isoindoline and dihydrobenzazepine derivatives. A preliminary test on Pd NPs leaching into the solution (1.7 × 10 − 3 mg) seems to indicate that, at the end of the reaction, almost all of the active metal is present on the ﬁber surface.

In all cases described so far, homogeneous organometallic species hav employed as catalysts, thus making its recovery impossible and resulting in th contamination of the products. The research of greener methodologies prompt investigate the possible use of palladium nanoparticles (Pd NPs) deposited o scavengers as catalysts. Commercially available mercapto-functionalized po fibers, Smopex ® -111 and Smopex ® -234 ( Figure 2), have been chosen as supports; th been developed for the recovery of platinum group metals (Pt, Pd, Rh) from postsolutions of cross-coupling processes, such as Mizoroki-Heck, Suzuki-Miyau Sonogashira reactions [89][90][91][92]. Pd NPs supported on Smopex ® -111 and Smopex ® -2 obtained through the metal vapor synthesis (MVS) technique. The versatility and fe of this synthetic approach in depositing size-controlled Pd NPs onto a wide r supports, including organic polymers, have been previously established [93][94][95][96][97][98][99][100].
In the present work, we report that Pd/Smopex ® -234 has resulted in an catalyst for the synthesis of phthalan, isochroman, and isoindoline derivatives cyclocarbonylative Sonogashira reactions. The Pd NPs' dispersion, as well as the natu thiol moiety present on the polyolefin fibers, strongly influence the efficiency of the reactions. Nitrogen-containing heterocycles are important substructures that are found in natural and synthetic alkaloids [45,46]. They also serve as an important source of pharmaceuticals and have inspired synthetic chemists to develop novel chemical transformations. For instance, indole [47][48][49] and its derivatives, such as isoindole [50,51] and isoindoline [52] (Figure 1c), are the basis for compounds possessing relevant biological activities. In particular, isoindoline derivatives are inhibitors of several enzymes involved in numerous diseases, including diabetes, obesity, heart failure, cancer, and mood disorders [53]. Moreover, isoindoline-based ligands are very interesting due to their modular set-up [54]. Finally, isoindoline pigments are particularly relevant, since they cover a wide range of colors from greenish-yellow to red and brown [55].
In all cases described so far, homogeneous organometallic species have been employed as catalysts, thus making its recovery impossible and resulting in the metal contamination of the products. The research of greener methodologies prompted us to investigate the possible use of palladium nanoparticles (Pd NPs) deposited on metal scavengers as catalysts. Commercially available mercapto-functionalized polyolefin fibers, Smopex ® -111 and Smopex ® -234 ( Figure 2), have been chosen as supports; they have been developed for the recovery of platinum group metals (Pt, Pd, Rh) from post-reaction solutions of cross-coupling processes, such as Mizoroki-Heck, Suzuki-Miyaura, and Sonogashira reactions [89][90][91][92]. Pd NPs supported on Smopex ® -111 and Smopex ® -234 were obtained through the metal vapor synthesis (MVS) technique. The versatility and feasibility of this synthetic approach in depositing size-controlled Pd NPs onto a wide range of supports, including organic polymers, have been previously established [93][94][95][96][97][98][99][100].  In the present work, we report that Pd/Smopex ® -234 has resulted in an efficient catalyst for the synthesis of phthalan, isochroman, and isoindoline derivatives through cyclocarbonylative Sonogashira reactions. The Pd NPs' dispersion, as well as the nature of the thiol moiety present on the polyolefin fibers, strongly influence the efficiency of the catalytic reactions.

Synthesis and Morphology of the Catalysts
Palladium NPs were obtained according to the MVS technique ( Figure 3). This approach allowed for the generation of Pd nanoclusters that were weakly stabilized by organic solvents, which were then dispersed on Smopex ® -111 and Smopex ® -234 supports, respectively, by simple impregnation at 25 • C. Further reduction or thermal treatments of the catalysts were not required.

Synthesis and Morphology of the Catalysts
Palladium NPs were obtained according to the MVS technique ( Figure 3). This approach allowed for the generation of Pd nanoclusters that were weakly stabilized by organic solvents, which were then dispersed on Smopex ® -111 and Smopex ® -234 supports, respectively, by simple impregnation at 25 °C. Further reduction or thermal treatments of the catalysts were not required. More in detail, Palladium vapors were co-condensed at a low temperature (77 K) with vapors of weakly stabilizing organic ligands (i.e., a mixture of mesitylene and 1hexene) using a commercially available glass reactor. Upon warming, the frozen matrix melted and the nucleation and growth processes of the metal particles occurred, affording metal nanoclusters that were weakly stabilized by the solvent molecules, called solvated metal atoms (SMAs). The interaction of the metal vapors with the solvent matrix very quickly quenched the kinetic energy of metal atoms. The final sizes of the metal aggregates were greatly influenced by the solvent employed and the amount used, allowing for good control over their size. The Pd-SMA was handled at a low temperature (between 223 and 243 K) under an inert atmosphere, and it was used as a precursor for the preparation of supported Pd nanoparticles by simply mixing the SMA with the solid supports (i.e., Pd/Smopex ® -234 and Pd/Smopex ® -111) at room temperature. The metal quickly separated quantitatively from the solvent by interacting with the support surface, thus affording solid catalytic systems without the need for poisons (i.e., halide from metal salt precursors in catalysts prepared through reduction methods). One of the main advantages of the MVS approach is that it allows for the preparation of supported catalytic systems where the metal is deposited directly in its reduced form, so that the calcination and activation processes of the conventional wet deposition method are not required.
The  More in detail, Palladium vapors were co-condensed at a low temperature (77 K) with vapors of weakly stabilizing organic ligands (i.e., a mixture of mesitylene and 1-hexene) using a commercially available glass reactor. Upon warming, the frozen matrix melted and the nucleation and growth processes of the metal particles occurred, affording metal nanoclusters that were weakly stabilized by the solvent molecules, called solvated metal atoms (SMAs). The interaction of the metal vapors with the solvent matrix very quickly quenched the kinetic energy of metal atoms. The final sizes of the metal aggregates were greatly influenced by the solvent employed and the amount used, allowing for good control over their size. The Pd-SMA was handled at a low temperature (between 223 and 243 K) under an inert atmosphere, and it was used as a precursor for the preparation of supported Pd nanoparticles by simply mixing the SMA with the solid supports (i.e., Pd/Smopex ® -234 and Pd/Smopex ® -111) at room temperature. The metal quickly separated quantitatively from the solvent by interacting with the support surface, thus affording solid catalytic systems without the need for poisons (i.e., halide from metal salt precursors in catalysts prepared through reduction methods). One of the main advantages of the MVS approach is that it allows for the preparation of supported catalytic systems where the metal is deposited directly in its reduced form, so that the calcination and activation processes of the conventional wet deposition method are not required.
The The presence of large agglomerates of roundish NPs, having diameters that were less than 10 nm in size (d m = 3.5 nm), was detected ( Figure 4a).
On the other hand, the analysis of Pd/Smopex ® -234 revealed the great affinity of this support for the as-prepared MVS-derived Pd NPs (Figure 4b), which prevents further NP aggregation phenomena during their immobilization. Indeed, a highly homogeneous dispersion of small Pd NPs (d m = 1.5 nm), which densely populated the surface of the organic fiber, was detected. Indeed, the mercaptoethyl acrylate group of Smopex ® -234 is able to chelate the Pd NPs much better than the thiol functional group of Smopex ® -111. Therefore, on Smopex ® -234 Pd NPs are highly dispersed and stabilized. Moreover, assuming that the Pd NPs were spherical in shape, the theoretical exposed Pd fraction and metal-specific surface areas (SSAs) for both catalysts were calculated from HRTEM data through applying the following Equation (1): d VS /d at = 3.32/(FE) 1.23 (1) where d VS is the size of Pd crystallites, d at is the atomic diameter of Pd (i.e., 0.275 nm), and FE is the exposed fraction of Pd [101], and Equation (2): where r i is the mean radius of the size class containing n i particles, and ρ Pd is the volumetric mass of Pd (12.02 g/cm 3   On the other hand, the analysis of Pd/Smopex ® -234 revealed the great affinity of th support for the as-prepared MVS-derived Pd NPs (Figure 4b), which prevents further N aggregation phenomena during their immobilization. Indeed, a highly homogeneou dispersion of small Pd NPs (dm = 1.5 nm), which densely populated the surface of th organic fiber, was detected. Indeed, the mercaptoethyl acrylate group of Smopex ® -234 able to chelate the Pd NPs much better than the thiol functional group of Smopex ® -11 Therefore, on Smopex ® -234 Pd NPs are highly dispersed and stabilized. Moreove assuming that the Pd NPs were spherical in shape, the theoretical exposed Pd fraction an metal-specific surface areas (SSAs) for both catalysts were calculated from HRTEM da through applying the following Equation (1):    (Table  1, entry 2), those deposited on the Smopex ® -234 fiber showed high catalytic efficiency in promoting the synthesis of phthalan derivative 3aa quantitatively, even in the presence of a very low amount of catalyst (0.2 mol%).  [102,103] (Z)-3aa (75%) with respect to the reaction carried out with the homogeneous catalyst (65%). The increase of the (Z) isomer amount after purification (i.e., silica column chromatography) may be due to the interconversion of (E) stereoisomer into the (Z) one, as already reported in the literature [104]. Indeed, as can be verified in the 1 H-NMR of the crude product (see Supplementary Materials) the composition of the two isomers changes after purification, probably due to traces of acid. The observed catalytic trend was confirmed by the reactions carried out using functionalized iodoarenes 2b and 2c (Table 1, entries 4-5), which possess different stereoelectronic features. Pd/Smopex ® -234 was able to catalyze the cyclocarbonylative reactions quantitatively, affording the corresponding phthalans, (Z)-3ab and (Z)-3ac, in high yields (70-82%) after purification. Moreover, in the case of nitrile derivative 3ac, a complete stereoselectivity towards the (Z) isomer was observed.  [102,103] (Z)-3aa (75%) with respect to the reaction carried out with the homogeneous catalyst (65%). The increase of the (Z) isomer amount after purification (i.e., silica column chromatography) may be due to the interconversion of (E) stereoisomer into the (Z) one, as already reported in the literature [104]. Indeed, as can be verified in the 1 H-NMR of the crude product (see Supplementary Materials) the composition of the two isomers changes after purification, probably due to traces of acid.
The catalytic activity of Pd/Smopex ® -234 was subsequently tested in the reaction of t-butylbenzyl alcohol 1b with iodobenzene 2a (Table 1, entries [8][9]. The stereoselectivity of the process favored the formation of the (E) isomer in all the reactions ((Z)/(E) ratio of about 20/80), probably due to the steric hindrance of benzyl alcohol 1b. The same factor could be the reason for the overall reduced rate of the catalytic cycle. Indeed, in the cases of both PdCl 2 (PPh 3 ) 2 -and Pd/Smopex ® -234-promoted reactions, a substrate conversion of almost 20% was observed when a 0.2 mol% of palladium was used. (Table 1, entries 6 and 8). An increase of the catalytic amount to 0.5 mol% for the homogeneous complex determined a quantitative formation of phthalan 3ba (Table 1, entry 7). Analogously, an 82% conversion was observed when 1 mol% of Pd/Smopex ® -234 was used (Table 1, entry 9).
Prompted by the good results obtained in the synthesis of phthalans 3 promoted by Pd/Smopex ® -234 cyclocarbonylative Sonogashira reactions, we extended our investigation to the reaction of 2-(2-ethynylphenyl)ethanol 4 with iodoarenes 1a-c (Table 2), which was performed in the presence of homogeneous PdCl 2 (PPh 3 ) 2 and supported Pd/Smopex ® -234 catalysts. In all cases, the reactions showed a complete conversion of the precursors and the exclusive formation of the (Z) stereoisomer of isochromans 6a-c, which were isolated as pure products in very high yields (90-95%). To our delight, a very low amount of Pd/Smopex ® -234 (0.2 mol%) was able to catalyze the cyclocarbonylative reactions with complete chemo-and stereoselectivity. The catalytic activity of Pd/Smopex ® -234 was subsequently tested in the reaction of butylbenzyl alcohol 1b with iodobenzene 2a (Table 1, entries 8-9). The stereoselectivity o the process favored the formation of the (E) isomer in all the reactions ((Z)/(E) ratio of abou 20/80), probably due to the steric hindrance of benzyl alcohol 1b. The same factor could b the reason for the overall reduced rate of the catalytic cycle. Indeed, in the cases of bot PdCl2(PPh3)2and Pd/Smopex ® -234-promoted reactions, a substrate conversion of almos 20% was observed when a 0.2 mol% of palladium was used. (Table 1, entries 6 and 8). A increase of the catalytic amount to 0.5 mol% for the homogeneous complex determined quantitative formation of phthalan 3ba (Table 1, entry 7). Analogously, an 82% conversio was observed when 1 mol% of Pd/Smopex ® -234 was used (Table 1, entry 9).
Prompted by the good results obtained in the synthesis of phthalans 3 promoted b Pd/Smopex ® -234 cyclocarbonylative Sonogashira reactions, we extended our investigatio to the reaction of 2-(2-ethynylphenyl)ethanol 4 with iodoarenes 1a-c (Table 2), which wa performed in the presence of homogeneous PdCl2(PPh3)2 and supported Pd/Smopex ® -23 catalysts. In all cases, the reactions showed a complete conversion of the precursors and th exclusive formation of the (Z) stereoisomer of isochromans 6a-c, which were isolated a pure products in very high yields (90-95%). To our delight, a very low amount o Pd/Smopex ® -234 (0.2 mol%) was able to catalyze the cyclocarbonylative reactions wit complete chemo-and stereoselectivity. Finally, the protocol based on Pd/Smopex ® -234 cyclocarbonylative reactions wa applied to the preparation of nitrogen-containing heterocycles. For this purpose, ortho ethynylbenzyl tosylamide 6 and ortho-ethynylhomobenzyl tosylamide 7 were chosen a model compounds and tested in the reaction with iodobenzene 2a ( Table 3). First of all, 0 mol% of homogeneous PdCl2(PPh3)2 (Table 3,   The reactions were performed with ortho-ethynylhomobenzyl alcohol 4 (2 mmol) and iodoarene 2 (2 mmol), in Et 3 N (5 mL), under CO atmosphere (20 atm), and in the presence of 0.2 mol% of Pd, at 100 • for 24 h. 2 Pd/Smopex ® -234 contains 1% w/w of palladium. 3 The yields of pure products are reported.
Finally, the protocol based on Pd/Smopex ® -234 cyclocarbonylative reactions was applied to the preparation of nitrogen-containing heterocycles. For this purpose, orthoethynylbenzyl tosylamide 6 and ortho-ethynylhomobenzyl tosylamide 7 were chosen as model compounds and tested in the reaction with iodobenzene 2a ( Table 3). First of all, 0.2 mol% of homogeneous PdCl 2 (PPh 3 ) 2 (Table 3, entry 1) and supported Pd/Smopex ® -234 (Table 3, entry 2) were employed in the reaction of tosylamide 6 with 2a, under the same experimental conditions (for 4 h at 100 • C, under 20 atm of CO, in Et 3 N, and using toluene as solvents). A relevant reduction of the reaction rate was detected when cyclocarbonylation was carried out with Pd NPs supported on Smopex ® -234. Nevertheless, (E)-1-phenyl-2-(2-tosylisoindolin-1-ylidene) ethanone 8 was obtained as an exclusive product. In order to improve the conversion of the process, the reaction was repeated with 0.4 mol% of Pd/Smopex ® -234 for a longer reaction time (24 h); under these experimental conditions, the quantitative formation of isoindoline derivative 8 was finally achieved (Table 3, entry 4).
The Pd/Smopex ® -234 catalyst was subsequently applied to the cyclocarbonylative Sonogashira reaction between tosylamide 7 and iodobenzene 2a. The reaction took place with 0.4 mol% of supported Pd NPs and solely yielded dihydrobenzazepine 9, which is an important nucleus of many biologically active natural products and pharmaceutical compounds [105,106]. Table 3. Palladium-promoted synthesis of N-heterocyclic compounds via cyclocarbonylative Sonogashira reactions. and the hot reaction mixture was filtered (using a Teflon filter, 0.2 mm) under nitrogen atmosphere. The palladium content in the resulting solution was determined by ICP-OES analysis and was found to be 0.8 w/w% of the initial Pd (i.e., 1.7 10 −3 mg). This very low value will prompt us to carry out further experiments, such as recycling of the catalyst and Maitlis hot filtration tests [107,108], to evaluate the mechanism (homogeneous or heterogeneous) of the Pd/Smopex ® -234 catalyst in the cyclocarbonylative Sonogashira reaction.  3 Conversion was estimated through the 1 H-NMR analysis of crude products. 4 The yields of pure products are reported in parentheses. 5 Dihydrobenzazepine 9 was obtained as a mixture of two conformers: s-trans/s-cis (60/40 molar ratio).

Preparation of Solvated Palladium Atoms Solutions
Palladium vapors were generated under reduced pressure (10 −5 mBar) through the resistive heating of 500 mg of the metal in an alumina-coated tungsten crucible; they were then co-condensed at liquid N2 temperature (−195 °C) with vapors of 1-hexene (30 mL) and mesitylene (30 mL) in a glass reactor [109]. The reactor chamber was heated to the melting point of the solid matrix (−40 °C), and the resulting brown solution (called Pd-SMA) was siphoned and handled at a low temperature (about −40 °C). The palladium content of the obtained Pd-SMA, determined through an ICP-OES analysis, was 2.3 mg of Pd/mL.  3 Conversion was estimated through the 1 H-NMR analysis of crude products. 4 The yields of pure products are reported in parentheses. 5 Dihydrobenzazepine 9 was obtained as a mixture of two conformers: s-trans/s-cis (60/40 molar ratio).
Finally, preliminary tests of Palladium leaching and catalyst recovery at the end of the reaction were carried out. With this aim, the autoclave was charged with iodobenzene 2a (0.6 mmol), tosylamide 6 (0.5 mmol), Et 3 N (1.5 mL), toluene (1.0 mL), and Pd/Smopex ® -234 (0.4 mol% of Pd). After 24 h at 100 • C, the CO pressure was discharged (under fume hood), and the hot reaction mixture was filtered (using a Teflon filter, 0.2 mm) under nitrogen atmosphere. The palladium content in the resulting solution was determined by ICP-OES analysis and was found to be 0.8 w/w% of the initial Pd (i.e., 1.7 × 10 −3 mg). This very low value will prompt us to carry out further experiments, such as recycling of the catalyst and Maitlis hot filtration tests [107,108], to evaluate the mechanism (homogeneous or heterogeneous) of the Pd/Smopex ® -234 catalyst in the cyclocarbonylative Sonogashira reaction.

Preparation of Solvated Palladium Atoms Solutions
Palladium vapors were generated under reduced pressure (10 −5 mBar) through the resistive heating of 500 mg of the metal in an alumina-coated tungsten crucible; they were then co-condensed at liquid N 2 temperature (−195 • C) with vapors of 1-hexene (30 mL) and mesitylene (30 mL) in a glass reactor [109]. The reactor chamber was heated to the melting point of the solid matrix (−40 • C), and the resulting brown solution (called Pd-SMA) was siphoned and handled at a low temperature (about −40 • C). The palladium content of the obtained Pd-SMA, determined through an ICP-OES analysis, was 2.3 mg of Pd/mL.

Synthesis of Phthalans: General Procedure
In a typical run (see Table 1), ortho-ethynylbenzyl alcohol 1 (2.0 mmol), iodoarene 2 (2.0 mmol), and Et 3 N (5 mL) were mixed, under CO atmosphere, into a Schlenk tube. This solution was siphoned in a 25 mL stainless steel autoclave, previously charged with the Pd catalyst (0.2-1 mol%), and placed under vacuum (0.1 Torr). The reactor was pressurized with carbon monoxide (20 atm), and the resulting mixture was stirred at 100 • C for 24 h. After the removal of excess CO (under fume hood), the reaction mixture was diluted with CH 2 Cl 2 (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure. Reagent conversion and product composition were determined through 1 H-NMR analysis. Crude products were purified through column chromatography on silica gel and were characterized by 1 H-NMR and 13 C-NMR techniques.

Synthesis of Isochromans: General Procedure
In a typical run (see Table 2), 2-(2-ethynylphenyl)ethanol 4 (2.0 mmol), iodoarene 2 (2.0 mmol), and Et 3 N (5 mL) were mixed, under CO atmosphere, into a Schlenk tube. This solution was siphoned in a 25 mL stainless steel autoclave, previously charged with the Pd catalyst (0.2 mol%), and placed under vacuum (0.1 Torr). The reactor was pressurized with carbon monoxide (20 atm), and the resulting mixture was stirred at 100 • C for 24 h. After the removal of excess CO (under fume hood), the reaction mixture was diluted with CH 2 Cl 2 (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure. Reagent conversion and product composition were determined through 1 H-NMR analysis. Crude products were purified through column chromatography on silica gel and were characterized by 1 H-NMR and 13 C-NMR techniques.

Synthesis of N-Heterocyclic Compounds: General Procedure
In a typical run (see Table 3), ortho-ethynyl(homo)benzyl tosylamide 6 or 7 (2.0 mmol), iodobenzene 2a (2.5 mmol), Et 3 N (3 mL), and toluene (2 mL) were mixed, under CO atmosphere, into a Schlenk tube. This solution was siphoned in a 25 mL stainless steel autoclave, previously charged with the Pd catalyst (0.2-0.4 mol%), and placed under vacuum (0.1 Torr). The reactor was pressurized with carbon monoxide (20 atm), and the resulting mixture was stirred at 100 • C for a selected time (4-24 h). After the removal of excess CO (under fume hood), the reaction mixture was diluted with CH 2 Cl 2 (20 mL), washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure. Reagent conversion and product composition were determined through 1 H-NMR analysis. Crude products were purified through column chromatography on silica gel or neutral alumina and were characterized through 1 H-NMR and 13 C-NMR techniques.

Conclusions
In conclusion, we have reported that Pd NPs, prepared according to the MVS technique, can be easily deposited on commercial thiol-based metal scavengers Smopex ® -111 and Smopex ® -234, affording Pd/Smopex ® -111 and Pd/Smopex ® -234 systems. The latter material exhibits a very high homogeneous dispersion of small Pd NPs (d m = 1.5 nm) without the presence of Pd NP aggregates, as observed for Pd/Smopex ® -111. Both systems were initially studied as supported catalysts in the cyclocarbonylative reaction of 2-ethynylbenzyl alcohol with iodoarenes to generate phthalans. Pd/Smopex ® -234 showed a catalytic efficiency comparable to that observed with the PdCl 2 (PPh 3 ) 2 organometallic complex, which was used as a reference homogeneous catalyst. On the other hand, Pd/Smopex ® -111 was completely unable to promote the reaction. Pd/Smopex ® -234 also proved to be very efficient in the synthesis of isochroman, isoindoline, and dihydrobenzazepine derivatives with high chemo-and stereoselectivity.
Almost all the cyclocarbonylative Sonogashira reactions were carried out with a very small amount of catalyst (0.2-0.4 mol% of Pd) in both phosphine-free and Cu-free conditions, thus enhancing the potentialities of Pd/Smopex ® -234 as a promising catalyst for heterocycle synthesis.