One-pot preparation of β –amido ketones and esters in four-component condensation reaction using ferric hydrogensulfate as effective and reusable catalyst

A new one-pot and efficient four-component condensation of benzaldehyde derivatives, enolizable ketones, acetyl chloride and acetonitrile or benzonitrile in the presence of ferric hydrogensulfate as an inexpensive and effective catalyst for the synthesis of β -amido ketones and esters is described. The present methodology offers several advantages, such as good yields, short reaction times and a recyclable catalyst with a very easy work up.


Introduction
Multi-component reactions (MCRs) are important for the achievement of high levels of brevity and diversity.They allow more than two simple and flexible building blocks to be combined in practical, time-saving one-pot operations, giving rise to complex structures by simultaneous formation of two or more bonds, according to the domino principle. 1MCRs contribute to the requirements of an environmentally friendly process by reducing the number of synthetic steps, energy consumption and waste production.Researchers have transformed this powerful technology into one of the most efficient and economic tools for combinatorial and parallel synthesis. 1,2Due to their inherent simple experimental procedures and their one-pot character, they are perfectly suited for automated synthesis.][3][4][5][6][7][8] Amido-or amino ketone derivatives are important for their biological, pharmaceutical properties, 9,10 and in the preparation of antibiotic drugs such as nikomycine or neopolyoxines. 11,12The common procedure for the synthesis of these class compounds is the Dakin-West reaction [13][14][15] which involves the condensation of α-amino acids with acetic anhydride in the presence of suitable base, [3][4][5][6][7][8][9][10][11][12][13][14][15][16] these reaction produce α-acetamido ketones through an intermediate azalactone. 16Recently, other synthetic methods have been used for the formation of β-amido ketones through the multi-component condensation of aryl aldehydes, enolizable ketones and acetyl chlorides in acetonitrile in the presence of Lewis or Brønsted acid catalysts such as CoCl 2 , 17,18 montmorillonite K-10 clay, 19 silica sulfuric acid, 20 BiCl 3 generated from BiOCl, 21 ZrOCl 2 .8H2O, 224][35][36][37] Ferric hydrogensulfate gained much interest in the Friedel-Crafts acylation of alkoxy benzenes by aliphatic anhydrides, 38 but there are a few reports on the application of this inorganic acidic salt in the literature. 38Ferric hydrogensulfate as a recyclable solid Brønsted acid catalyst is safe, easy to handle, environmentally benign and presents fewer disposal problems.This catalyst was prepared from the reaction of anhydrous ferric chloride (1 mmol) with concentrated sulfuric acid (3 mmol). 38This salt is stable and non-hygroscopic solid material, insoluble in most organic solvents.Herein, we wish to describe a new, simple, mild and effective procedure for the one-pot synthesis of β-amido ketones via a four-component condensation reaction between aldehydes, enolizable ketones, acetyl chloride and acetonitrile or benzonitrile in the presence of ferric hydrogensulfate as catalyst (Scheme 1).The MCRs for the preparation of β-amido ketones were carried out under reflux condition at 80 o C.
As shown in Table 2, aromatic aldehydes and acetophenone derivatives with both electronwithdrawing and electron-donating substituents afforded to the corresponding β-amido ketones without the formation of any side products, in high to excellent yields at reflux conditions (Table 2, Entries 1-16).Phenolic -OH groups under present reaction conditions were converted to acetate (-OAc) groups (Table 2, Entry 16).
Under the optimized reaction conditions, by using benzonitrile in place of acetonitrile, aldehydes were transformed to their corresponding β-benzamido ketones in high yield (Table 2, Entries 17-20).
Interestingly, during the course of our study, we have noticed that when the 2pyridinecarbaldehyde is treated with acetophenone under the same experimental conditions, the reaction was stopped and the catalyst was destroyed and loss its activity.We also added pyridine to the standard of reaction conditions (benzaldehyde/acetophenone/acetyl chloride/acetonitrile/catalyst), after a few minutes, pyridine destroys the catalyst and inhibit the preparation of N-(3-oxo-1,3-diphenyl-propyl)-acetamide (Table 2, Entry 21).Yields refer to the pure isolated products.b The references of known products in the literature.c Using PhCN (~ 3equiv) in CH 2 Cl 2 (5 mL).
We also studied the multi-component reaction of aromatic aldehydes, other enolizable ketones (propiophenone, methyl acetoacetate and cyclohexanone) and acetonitrile in the presence of acetyl chloride and Fe(HSO 4 ) 3 as catalyst.In all cases, mixtures of syn and anti diastereomers were obtained, whilst the diastereoselectivity depended upon the nature of the reactants.The amount of these syn and anti products was determined by 1 HNMR spectra, the coupling constant between H-2 and H-3 is 6-9Hz for an anti isomer, while 2-5 Hz for a syn isomer [17-19].As it was shown in table 3, an anti diastereomer was found to be major product.Methyl acetoacetate afforded the corresponding β-acetamido esters in good yields with high diastereoselectivity.The anti/syn ratio was determined from 1 HNMR spectrum of crude reaction mixture.
In a typical experiment, after a period of time that the reaction was completed, the mixture was filtered and heterogeneous catalyst was recovered.Then, the residue solution was poured into the cooled water until solid crude product was formed.In every experiment whole of the ferric hydrogensulfate was easily recovered from the reaction mixture.The reusability of the catalysts is one of the most important benefits and makes them useful for commercial applications.Thus the recovery and reusability of ferric hydrogensulfate was investigated.The separated catalyst can be reused after washing with CHCl 3 and drying at 100 o C. The reusability of the catalyst was checked by the reaction of benzaldehyde and acetophenone in the presence of acetyl chloride and acetonitrile using 25 mol% of Fe(HSO 4 ) 3 under reflux condition at 80 o C. The results indicate that the catalyst can be used five times without any loss of its activity (Table 4).

27(%) a
Yields are reported after aqueous work-up.b Ratio obtained from 1 H NMR of the crude reaction mixture; All syn and anti diastereomers have been reported previously in the literatures 17,19,22,25,27,28 and 32 thus we compared 1 NMR spectra with authentic samples.In summary, we have demonstrated a new and important catalytic activity of ferric hydrogensulfate as an inexpensive, commercially available, reusable and non-corrosive catalyst for the synthesis of β-amido ketones in high to excellent yields under almost mild reaction conditions.The simple experimental procedure combined with the easy work-up and high to excellent yields of products are strong features of the presented method.

Preparation of ferric hydrogensulfate
A 50 mL suction flask was equipped with a dropping funnel.The gas outlet was connected to a vacuum system through an alkaline solution trap.Anhydrous ferric chloride (10 mmol) was charged into the flask and concentrated sulfuric acid 98% (30 mmol) was added dropwise over a period of 30 min at room temperature.HCl evolved immediately.After completion of the addition, the mixture was shaken for 30 min at 100 o C, while the residual HCl was eliminated by suction.Finally, a pale-brown solid Fe(HSO 4 ) 3 was obtained. 36

Catalyst characterization
This paper report catalyst characterization of Fe(HSO 4 ) 3 for the first time.

X-Ray diffraction (XRD)
Powder X-Ray Diffraction (XRD) measurements were performed using D8 Advance diffract meter made by a Bruker axs company in Germany.Scans were taken with a 2θ step size of 0.02 and a counting time of 1.0s using CuK α radiation source generated at 40KV and 30mA.Specimens for XRD were prepared by compaction in to a glass-backed aluminium sample holder.Data was collected over a 2θ range from 4º to 70º and phases were identified by matching experimental patterns to entries in the Diffract plus version 6.0 indexing soft ware.The catalyst which was prepared characterized by XRD and pattern is presented in figure 1.As it was shown in the figure 1, the actual phases for this catalyst was identified under the specified preparation conditions were Fe(HSO 4 ) 3 (tetragonal) and Fe 2 (SO 4 ) 3 (monoclinic) that the Fe 2 (SO 4 ) 3 (monoclinic) phase is highly selective for producing of product.The weight change of catalyst precursors were measured using a TGA/DSC simultaneous thermal analyzer apparatus of Rheometric Scientific Company (STA 1500+ Model) under a flow of dry air.The sample weight was chosen 25 mg and the temperature was raised from room temperature to 500 ºC using a linear programmer at a heating rate of 10 ºC/min.The TGA and DSC curves for the catalyst are illustrated in figure 2. The weight losses found from TGA measurements agree fairly well with those expected for the decomposition of Fe(HSO 4 ) 3 , to different oxides of iron and sulphate.The thermo gravimetric curve of catalyst showed two-stage decomposition which considered to be due to removal of physical absorbed water (80-120 °C) or basic Fe(HSO 4 ) 3 (140-330 °C), respectively.DSC measurement was preformed in order to provide further evidence for the presence of the various species and evaluates their thermal behaviour.It shown in figure 2, the endothermic peak at lower temperature represents the removal of the physically adsorbed water from the material, while the endothermic peak at higher temperature represents solely the decomposition of the Fe(HSO 4 ) 3 to different oxides of iron and sulfate.
Specific surface area, total pore volume and pore size Brunauer-Emmett-Teller surface area BET measurements and the pore size in catalyst were conducted using a micro metrics adsorption equipment (Quantachrome instrument, model Nova 2000, USA) determining nitrogen (99.99% purity) as the analysis gas and the catalyst samples were slowly heated to 120 ºC for 3h under nitrogen atmospheric.The BET specific surface area measurements of different precursors and catalysts were evacuated at -196 ºC for 300 minutes.Characterization of catalyst was carried out using BET measurements and the BET specific surface area, total pore volume and average pore diameter are presented in Table 6.Results were shown that the catalyst have a good specific surface area and high pore volume, this might be a reason for high catalytic performance of catalyst.

FT-IR spectrum of Fe(HSO 4 ) 3
The FT-IR spectrum of the catalyst was shown in figure 3. The catalyst is solid and solid state IR spectrum was recorded using the KBr disk technique.The spectrum shows a broad OH stretching absorption around 3500 and 3100 cm -1 .For sulfuric acid functional group in Fe(HSO 4 ) 3 , the FT-IR absorption of the O=S=O stretching modes lies in 1140 cm −1 , and that of the S-O stretching mode lies in 600-700 cm −1 .

Table 1 .
Preparation of N-(3-oxo-1,3-diphenylpropyl)acetamide from the reaction of benzaldehyde and acetophenone in the presence of acetyl chloride and acetonitrile using variety amount of Fe(HSO 4 ) 3 under reflux condition at 80 o C

Table 2 .
Preparation of β-amido ketones from aldehydes and enolizable ketones in the presence of acetyl chloride and acetonitrile or benzonitrile catalyzed using ferric hydrogensulfate under reflux conditions

Table 4 .
Recyclability of the catalyst in the reaction of benzaldehyde and acetophenone in the presence of acetyl chloride and acetonitrile using25mol% of Fe(HSO 4 ) 3 under reflux condition at 80 o C To show the merit of the present work in comparison with reported results in the literature, we compared results of ferric hydrogensulfate with BiOCl, 21 ZrOCl 2 .8H 2 O, 22 CeCl 3. 7H 2 O, 28 ZnO 29 and I 2 31 in the synthesis of β-acetamido ketone derivatives.As shown in Table 5, ferric hydrogensulfate can act as effective catalyst with respect to reaction times, yields and the obtained products.

Table 6 .
Specific surface area, total pore volume and pore size of the ferric hydrogensulfate