Decarbonylation of Aromatic Aldehydes and Dehalogenation of Aryl Halides Using Maghemite-Supported Palladium Catalyst

Abstract A facile decarbonylation reaction of a variety of aromatic and heteroaromatic aldehydes using maghemite-supported palladium catalyst has been developed. The magnetic properties of catalyst facilitated an easy and efficient recovery of the catalyst from the reaction mixture using an external magnet. It was found that the catalyst could be reused up to four consecutive catalytic runs without a significant change in activity. In addition, the catalyst was also very effective in the dehalogenation of aryl halides. This is the first report on efficient utilization of directly immobilized Pd on maghemite in decarbonylation and dehalogenation reactions.

The cytochrome P450 enzymes play an important role in the decarbonylation pathway in biological systems. 1 The decarbonylation of aldehydes is of great importance in synthetic organic chemistry and pharmaceutical industry as well. The transition-metal-mediated decarbonylation of aldehydes has been extensively investigated and established as a useful synthetic transformation. 2 The first rhodiummediated decarbonylation reaction was reported by Tsuji and Ohno in 1965 using a stoichiometric amount of Wilkinson's catalyst, and over the past 50 years this method has been the most frequently employed. 3 Efficient catalytic decarbonylation of aldehydes has been accomplished with more reactive cationic Rh complexes. 4 In addition, the decarbonylation of aldehydes has been successfully performed with palladium, 5 iridium, 6 nickel, 7 and ruthenium 8 catalysts. Recently, silica-and zirconia-supported Pd catalysts have been developed for decarbonylation of aromatic aldehydes. 9 Over the past few years, magnetic supported nanocatalysts have attracted considerable attention because of the ease of their preparation, high surface area to volume ratio, efficient separation from the reaction mixture with an external magnet, and recyclability. 10 In addition, their chemical inertness and thermal stability enable their use as highly effective catalysts in a wide range of synthetic transformations. In recent years, magnetically separable iron oxide maghemite (γ-Fe 2 O 3 ) has been widely utilized as an appealing and sustainable solid support material for metal nanocatalysts, owing to its easy production, nontoxic nature, and economical viability. The direct immobilization of metal nanocatalysts, which include Pd, 11 Cu, 12 Rh, 13 Zn, 14 and Au 15 on the magnetic surface, without the use of an external modifiers, has been recently reported, and the obtained catalysts were successfully used to perform various organic transformations. More recently, maghemite-supported Pd/PdO nanoparticles, 16 have been developed and the obtained catalyst was successfully used in the Heck-Mizoroki olefination, the Suzuki reaction, and the allylic oxidation of alkenes.
Within this study, we sought to determine if the directly immobilized magnetically recoverable Pd-catalyst could be efficiently utilized in the decarbonylation of aromatic aldehydes and in the dehalogenation of halogenoarenes.
The maghemite-supported palladium catalyst was prepared by the co-precipitation method (Scheme 1) recently reported by Rathi et al. 16 and characterized by inductively coupled plasma-quadrupole mass spectrometry (ICP-QMS) and scanning electron microscopy (SEM). SEM analysis showed that the surface area of catalyst was well developed, with sponge-like morphology and that the average crystallite size of the γ-Fe 2 O 3 was in the range of 1-10 μm, which was in agreement with the particle size distribution analysis (Figure 1, A and B). SEM analysis also showed that catalyst sample contained aggregated submicronic particles. The aggregates were up to 20 μm. Laser diffraction analysis showed that sample dispersed in ethanol by means of low energy ultrasound disintegrates to two main fractions. About 77% of sample mass make particles with mean size of 1.2-1.3 μm with standard deviation of 0.7 μm, and the rest of mass of 23% stays in aggregates with mean size of 14-17 μm with standard deviation of 10 μm. The ICP-QMS analysis confirmed the presence of 5.56 wt% Pd in the catalyst. The magnetic properties of maghemitesupported Pd catalysts facilitates an easy and efficient recovery of the catalyst from the reaction mixture using an external magnet (Figure 1, C). Initially, biphenyl-4-carboxaldehyde, prepared through the Suzuki-Miyaura cross-coupling reaction (Scheme 2), 16 was selected as a model substrate for optimization of reaction conditions for decarbonylation, and the results are presented in Table 1. Reactions were performed in the presence of 3-4 Å molecular sieves, as it has been found that the presence of molecular sieves greatly enhances the decarbonylation of aldehydes. 17

Scheme 2 Synthesis of biphenyl-4-carbaldehyde
Having established that palladium was necessary for catalysis (Table 1, entry 1), our next task involved identification of the optimal catalyst loading and solvent. It was found that the decarbonylation could be smoothly promot-ed by using 3.6 mol% of Pd/γ-Fe 2 O 3 in cyclohexane at 130 °C (entry 2). Increasing the catalyst loading to 5.0 mol% was necessary to obtain full conversion (entry 3). Regarding the solvent, it can be changed to toluene and 1,4-dioxane, albeit in slightly decreased yields (entries 4 and 5).
With the optimized reaction conditions in hand ( Table  1, entry 3) the scope of the substrates for the decarbonylation of aromatic aldehydes catalyzed by Pd/γ-Fe 2 O 3 was investigated (Scheme 3).
High to excellent yields of the decarbonylated products were obtained with different aryl aldehydes (Scheme 3, 4ad). Reactions in the presence of different functional groups including nitro, cyano, and ether are successful to generate the corresponding decarbonylated products (4e, 4g and 4h). Ortho-substituted aryl aldehydes were also transformed into decarbonylated products (4j and 4k) in good yields. Furthermore, heterocyclic aldehydes produced the desired decarbonylated products in good yields (4l-p) with the exception of benzo[b]thiophene-3-carboxaldehyde (4m).
Interestingly, no trace of the decarbonylated product was observed for halogen substituted aryl aldehydes (4f, 4i, and 4q), only starting compounds were identified. The drastic changes in reactivity observed with halogen-substituted aryl aldehydes suggested that the initial oxidative addition of the C-halogen bonds to palladium is more favorable than the addition of the C(O)-H bond (cf. Scheme 4, vide infra).
Separation, recovery, and reusability are very important properties of the catalyst from the economic, sustainability as well as the synthetic point of view. As mentioned, the catalyst was easily recovered from the reaction mixture using an external magnet (Figure 1, C). The catalyst was washed with absolute ethanol and dried under vacuum with heating at 50 °C until a complete dry mass was formed and reused for a consecutive run under the same reaction conditions.

Paper Syn thesis
As summarized in Figure 2 (A), it was found that the catalyst could be reused up to four consecutive catalytic runs without a significant change in activity during the decarbonylation of 4-tert-butylbenzaldehyde. The average GC-MS yield of the product for four consecutive runs was 91%, which clearly demonstrates the practical reusability of the catalyst. To find out the amount of palladium leached into the liquid we carried out ICP-QMS analysis of the filtrate remaining after the magnetic separation of the catalyst and it was found that the concentration of palladium in the filtrate was negligible (0.64 ppm).
The dehalogenation of aryl halides represents an important chemical transformation in organic synthesis. 18 While conducting our studies on the decarbonylation of aldehydes, we have noticed that, under the reaction conditions, the decarbonylation of the halogen-substituted aryl aldehydes was not promoted (Scheme 3, 4f, 4i, and 4q), and decided to further investigate the scope of the catalyst in dehalogenation chemistry ( Table 2).
The initial studies were conducted in propan-2-ol with Pd/γ-Fe 2 O 3 as the catalyst and NaOt-Bu as the base. Several aryl halides were successfully dehalogenated at room temperature. The catalyst system was effectively used for the dehalogenation of sterically hindered 2-bromo-1,3,5trimethylbenzene and the product was obtained in nearly quantitative yield ( Table 2, entry 1). Complete conversion of 2-bromo-1,3,5-trimethylbenzene into 1,3,5-trimethylbenzene was observed at 70 °C (entry 2). The heteroaryl bromide containing thiophene moiety was also subjected to the debromination at 70 °C to give the 2-phenylthiophene 4o in 84% yield (entry 12). Notably, using this catalytic system, 4o was obtained in good yields either via decarbonylation or by dehalogenation starting from 5-phenylthiophene-2-carbaldehyde and 2-bromo-5-phenylthiophene, respectively (Scheme 3, entry 4o and Table 2, entry 12). The regioselective dehalogenation of some polyhalogenated substrates was also examined. Good to high regioselectivity Scheme 3 Scope of Pd/γ-Fe 2 O 3 -catalyzed decarbonylation of aldehydes. a Isolated yield. b GC-MS yield (naphthalene was used as an internal standard). c GC-MS yield (methyl benzoate was used as an internal standard ). d Conversion based on GC-MS. e   V. Ajdačić et al.

Paper Syn thesis
was observed in the dehalogenation of 1-chloro-4-fluorobenzene, 1-bromo-4-chlorobenzene, and 1-chloro-4-iodobenzene, respectively (entries 3, 5, and 7) at room temperature. On the other hand, at elevated temperature the catalyst system showed low regioselectivity (entries 4, 6, and 8). Besides dehalogenated products 6b-d, the products of double dehalogenation 7a and 7b were also observed. However, the dehalogenation of 1-chloro-4-fluorobenzene produced fluorobenzene and benzene in nearly equal amounts. The transition-metal-catalyzed transformation of C-F bond represents a great challenge in organic chemistry, and the observed defluorination could be a useful approach in the transformation of aryl fluorides, which was confirmed with defluorination of 4-fluorotoluene and 4-fluoroanisole (entries 10 and 11). Notably, a complex reaction mixture was observed in the case of 4-bromobenzonitrile and methyl 4bromo-3-methylbenzoate probably due to instability of the cyano and ester groups under the applied reaction conditions.
As summarized in Figure 2 (B), it was found that the catalyst could be reused up to four consecutive catalytic runs without a significant change in activity during the dehalogenation of sterically hindered 2-bromo-1,3,5-trimethylbenzene.
On the basis of the above-mentioned results and relevant reports in the literature, 5h a possible mechanism for this methodology is presented in Scheme 4.

Scheme 4 Proposed mechanisms for decarbonylation and dehalogenation
As previously described, 16 the presence of ethanol during the preparation of the catalyst presumably leads to the reduction of Pd(II) to Pd(0). Oxidative addition of the C(O)-H bond of the aldehyde to the palladium gives the acylpalladium hydride complex, which subsequently undergoes CO migration. Reductive elimination then forms the decarbonylated product and CO desorption regenerates the catalyst. Oxidative addition of the aryl halide to the palladium gives the arylpalladium halide intermediate. Subsequently, base-promoted displacement of a halide anion generates an alkoxy-palladium species, which undergoes β-H elimination leading to an arylpalladium hydride complex. Finally, reductive elimination of the arene regenerates the catalyst. The reaction mechanism involving palladium clusters 9c is also possible and cannot be excluded at this time.

Paper Syn thesis
In conclusion, we have developed an easy and practical decarbonylation reaction by using retrievable maghemitesupported palladium catalyst. A number of aromatic and heteroaromatic aldehydes were successfully decarbonylated, without using any exogenous ligand for Pd. The catalyst was successfully recycled four times without loss of activity. In addition, the catalyst was also very effective in the dehalogenation of aryl halides. Finally, the observed defluorination could be a useful approach in the transformation of aryl fluorides.
Dry-flash chromatography was performed on SiO 2 (0.018-0.032 mm). Melting points were determined on a Boetius PMHK apparatus and are not corrected. IR spectra were recorded on a Thermo-Scientific Nicolet 6700 FT-IR Diamond Crystal instrument. 1 H and 13 C NMR spectra were recorded on a Bruker Ultrashield Avance III spectrometer (at 500 and 125 MHz, respectively) using CDCl 3 as the solvent and TMS as an internal standard. Chemical shifts are expressed in parts per million (ppm) on the (δ) scale. Chemical shifts were calibrated relative to those of the solvent. GC-MS spectra of the synthesized compounds were acquired on an Agilent Technologies 7890A apparatus equipped with a DB-5 MS column (30 m × 0.25 mm × 0.25 μm), a 5975C MSD and FID detector. The selected values are as follows: carrier gas was He (1.0 mL/min), temperature linearly increased from 40-315 °C (10 °C/min), injection volume: 1 μL, temperature: 250 °C, temperature (FID detector): 300 °C, and EI mass spectra range: m/z 40-550. For determination of Pd concentration ICP-QMS (iCAP Q, Thermo Scientific X series 2) was used. Instrument operating conditions for determination of Pd: RF power (W) = 1548; Gas flows (L/min) = 13.9, 1.09, 0.8; Acquisition time = 3 × 50 s; Points per peak = 3; Dwell time = 10 ns; Detector mode was analog/pulse; Replicates = 3. Measured isotope (normal mode): 104 Pd, 105 Pd, 106 Pd, 108 Pd, 110 Pd. The scanning electron microscope (SEM) images were obtained with a field emission scanning electron microscope SEM JEOL JSM-6610LV. Laser diffraction on particles was measured on Malvern Mastersize 2000 device in microPrecision measuring unit. 30 mg of sample was dispersed in 3 mL of ethanol for 30 min. Dispersions were added in the measuring unit until desired concentration was reached. Refractive index used for particles was 2.94 with adsorption coefficient 1. Resulting multimodal particle size distributions was then analyzed with normalmixEM (expectation maximization) method form Mixtools packet in R programming language. The experimental distributions was fitted as composition of two normal distribution, which corresponds to loosely aggregated and easily dispersed particles versus hard aggregates.
The syntheses of compounds 5-phenylfuran-2-carbaldehyde, 19 5phenylthiophene-2-carbaldehyde, 19 5-(4-fluorophenyl)thiophene-2carbaldehyde, 19 4-bromo-5-(4-fluorophenyl)thiophene-2-carbaldehyde, 20 and 5f 21 were described previously. 16 Maghemite was prepared by the co-precipitation method. Typically, FeSO 4 ·7H 2 O (6.06 g, 21.79 mmol) and FeCl 3 ·6H 2 O (11.75 g, 45.08 mmol) were dissolved in deionized H 2 O (120 mL) under an argon atmosphere. The resulting mixture was stirred for 15 min and heated at 60 °C under vigorous stirring. After attaining the desired temperature, aq NH 3 (30 mL, 25% NH 3 in water) was added dropwise, a black precipitate was immediately formed, and heating was continued for 2 h under an argon atmosphere. The precipitate was magnetically sepa-rated and washed thoroughly with deionized H 2 O until the supernatant liquor reached neutrality. The resulting material was dried under air at 100 °C for 12 h to give 5.38 g of maghemite. 16 A solution of PdCl 2 (349 mg) and KCl (1 g) in H 2 O (120 mL) was stirred for 5 min and maghemite (3 g) was added to it. The resulting mixture was stirred at r.t. for 1 h and the suspension was adjusted to pH 12-13 by the slow addition of aq 1 M NaOH and further stirred for 24 h. The aqueous layer was decanted with the help of an external magnet and the ensuing material was washed with deionized H 2 O (5 × 50 mL) under sonication at 45 °C followed by washing with EtOH and drying under reduced pressure at 60 °C for 4 h to afford 2.69 g of γ-Fe 2 O 3 -Pd. The ICP-QMS analysis confirmed the presence of 5.56 wt% Pd in the catalyst.

Recycling of γ-Fe 2 O 3 -Pd Catalyst for Decarbonylation of 4-tert-Butylbenzaldehyde
Reaction conditions were as follows: 4-tert-butylbenzaldehyde (0.18 mmol), γ-Fe 2 O 3 -Pd (17 mg, 5 mol% Pd), molecular sieves (3-4 Å, 100 mg), cyclohexane (1 mL), 130 °C, 24 h, argon. After the completion of the reaction, the reaction mixture was decanted with the help of an external magnet and the residue was washed with CH 2 Cl 2 , absolute EtOH, and dried under vacuum with heating at 50 °C until a complete dry mass was formed. The formed activated residue containing both the molecular sieves as well as the γ-Fe 2 O 3 -Pd catalyst was used for the second and further reaction cycles following the general reaction procedure.

Dehalogenation of 1-Chloro-4-fluorobenzene
Following the general procedure for dehalogenation, 5b was converted into 6b and 7a. GC-MS yields of 6b and 7a are 37% and 42%, respectively, based on naphthalene as standard.

Dehalogenation of 1-Bromo-4-chlorobenzene
Following the general procedure for dehalogenation, 5c was converted into 6c and 7a. GC-MS yields of 6c and 7a were 58% and 16%, respectively, based on methyl benzoate as standard.

Dehalogenation of 1-Chloro-4-iodobenzene
Following the general procedure for dehalogenation, 5d was converted into 6c and 7a. GC-MS yields of 6c and 7a were 60% and 18%, respectively, based on methyl benzoate as standard.

Dehalogenation of 2-Bromo-5-chlorotoluene
Following the general procedure for dehalogenation, 5e was converted into 6d and 7b. GC-MS yields of 6d and 7b were 21% and 40%, respectively, based on methyl benzoate as standard.

Dehalogenation of 4-Fluorotoluene
Following the general procedure for dehalogenation, 5f was converted into 7b. GC-MS yield of 7b was 100% based on naphthalene as standard.

Dehalogenation of 4-fluoroanisole
Following the general procedure for dehalogenation, 5g was converted into 4h. GC-MS yield of 4h was 100% based on methyl benzoate as standard.

Dehalogenation of 2-Bromo-5-phenylthiophene
For the dehalogenation of 2-bromo-5-phenylthiophene (5h), the typical procedure was followed. After completion of the reaction, the reaction mixture was decanted using an external magnet and the catalyst was washed with CH 2 Cl 2 (5 × 5 mL). The solution was washed with H 2 O (5 mL), brine (5 mL), dried (Na 2 SO 4 ), and the solvent was removed under reduced pressure. Compound 4o (16 mg, 84%) was obtained as a yellow crystalline powder. No further purification of the obtained crude product was required based on NMR analysis.