Cerium Chloride ( CeCl 3 . 7 H 2 O ) as a Highly Efficient Catalyst for One-Pot Three-Component Mannich Reaction

We have demonstrated the use of CeCl3· 7H2O as highly efficient catalyst for one-pot Mannich reaction to afford β-amino carbonyl compounds in good to excellent yield within shorter period of reaction time. The process is mild, efficient, environmentally benign with the use of little amount of catalyst.


Introduction
][3][4][5] Our research group focuses on finding efficient chemical transformation using three or more components in a single step by a catalytic process since it avoids use of stoichiometric toxic reagents, large amounts of solvents and expensive purification techniques which is also the fundamental targets of modern organic synthesis. 6here are many types of three-component reaction reported in the literature and Mannich reaction is one of the most important C-C bonds forming reaction.Basically, Mannich reaction is the synthesis of β-amino carbonyl compounds and as such is one of the most important reaction in organic synthesis. 7,8The gaining impetus of the Mannich reaction has been fuelled by the ubiquitous nature of nitrogen containing compounds in drugs 9 and natural products. 10owever, the classical Mannich reaction is plagued by a number of serious disadvantages with limited applications. 11,12Therefore, numerous modern versions of Mannich reaction have been developed to overcome the negative aspect of this classical method.In general, improved methodologies rely on two-component system using preformed electrophiles such as imines and stable nucleophiles such as enolates, enols, ethers and enamines, 13,14 but the preferable route is the use of a onepot three-component strategy as it facilitates wide range of structural variations, but these early three-component reactions were hampered due to a number of serious limitations. 15he conventional catalyst for the synthesis of β-amino carbonyl compounds of aldehydes, ketones and amines involve mainly organic and mineral acids like proline, [16][17][18] acetic acid, 19 p-dodecyl benzene sulfonic acid 20 and other Lewis acids. 21,22They often suffer the drawbacks of long reaction times, harsh reaction conditions, toxicity and difficulty in product isolation.While searching for economical and better catalyst, we thought its worthwhile to perform a controlled reaction for one-pot threecomponent Mannich reaction catalyzed by cerium(III) chloride heptahydrate (CeCl 3 • 7H 2 O), which has attracted considerable attention because of its diverse application as a promoter in organic synthesis. 23erium halides are relatively an effective Lewis acid catalyst, 24 as it is water tolerant, non-toxic, easy to handle, inexpensive and can be reused without further purification.
In this work, we have found CeCl 3 • 7H 2 O as an efficient catalyst for the synthesis of β-amino carbonyl compounds at room temperature through a one-pot three-component reaction of aromatic aldehydes, ketones and aromatic amines in methanol (Scheme 1).It is also noteworthy to mention that our environmentally benign reaction does not generate any toxic waste products.

Results and Discussion
In order to verify the efficient catalytic behavior of CeCl 3 • 7H 2 O, a controlled reaction was performed using benzaldehyde (1 mmol), aniline (1 mmol) and acetophenone (1 mmol) in methanol (5 mL) at room temperature.In the absence of CeCl 3 • 7H 2 O, the reaction resulted in the formation of a fused product after 8 h at 50 o C (10% yield).However under same condition by employing 1 mol% of CeCl 3 • 7H 2 O, the reaction afforded expected products up to 94% yield within 4 h of reaction time.
With this optimistic result in hand, we further investigated the best reaction conditions by using different amounts of CeCl 3 • 7H 2 O.An increase in the quantity of CeCl 3 • 7H 2 O from 1 mol% to 3 mol% not only decreased the reaction time from 4 h to 2 h but also increased the product yield slightly from 85% to 93%.Thus the use of 3 mol% CeCl 3 • 7H 2 O is sufficient to push the reaction forward for the optimum yield of β-amino carbonyl compounds (Table 1).
Further, we have also scrutinized this reaction by employing various Lewis acids such as CuSO 4 , CeCl Encouraged by these remarkable results, we screened a variety of aromatic aldehydes and amines having electron-withdrawing as well as electron-donating groups and in each case we observed good to excellent yields, however, when ortho-substituted anilines were used as substrates, the reaction gave no product probably due to steric hindrance of ortho-substituents.In the investigation of various substituted benzaldehydes, it was found that p-methylbenzaldehyde is the most reactive substrate in the reaction (Table 3, entry 3).It was observed that the catalyst had no catalytic activity for the reactions when aliphatic aldehydes and amines were used as substrate.
In order to ascertain the scope and limitation of this CeCl 3 of cyclohexanone with various aldehydes and amines as depicted in Table 3. Cyclohexanone showed antiselectivities determined by 1 H NMR analysis of crude products.Mannich reaction was very sensitive to reaction temperature.The high temperature could improve the reaction rate and shorten the reaction time, but favor side reactions and the oxygenolysis of aldehyde and amine. 25n our investigation for the effect of temperature we found that CeCl 3 • 7H 2 O efficiently catalyzed the Mannich reaction at room temperature.

Conclusions
In conclusion, we have developed a novel and efficient catalytic method for Mannich reaction of aldehydes, amines and ketones.We have shown that the reaction proceeds much faster when CeCl 3 • 7H 2 O is employed as a catalyst compare to uncatalyzed reaction.The most attractive part of this work is that only small amount of catalyst is needed for catalyzing the reaction.The simple experimental procedures, fast reaction rates and easy isolation of products make this procedure very useful and environment friendly.In addition, our method does not require expensive reagents and high temperature for the synthesis of β-amino carbonyl compounds compared to the traditional protocols and has broad substrate applicability with ease and much improved yields.

General experimental procedures
All chemicals were purchased from Sigma-Aldrich and Lancaster and were used as such.All reactions and purity of β-amino carbonyl compounds were monitored by thin layer chromatography (TLC) using aluminium plates coated with silica gel (Merck) using 20% and 80% petroleum ether as an eluent.The isolated products were further purified by column chromatography using silica gel G (particle size 10-40 microns, 300 mesh) purchased from Spectrochem Pvt. Ltd.Mumbai, India and purified product were recrystallized.Melting points are determined on Buchi 530.IR spectra were recorded on Perkin-Elmer FTIR-1710 spectrophotometer using KBr. 1 H NMR spectra were recorded on a Bruker Avance Spectrospin 300 (300 MHz) using TMS as internal standard and chemical shift are in d.GC-MS mass spectra were recorded on a Waters LCT Micromass.The temperature of the reaction mixture was measured through a non-contact infrared thermometer (AZ, Mini Gun type, Model 8868).

Typical experimental procedure for the synthesis of b-aminocarbonyls
In a 50 mL round bottom flask, acetophenone (1 mmol), aromatic aldehydes (1 mmol) and aromatic amines (1 mmol) in MeOH (5 mL) were mixed and stirred at room temperature.To this, CeCl 3 • 7H 2 O (cerium chloride heptahydrate) (3 mol%) was added.The progress of reaction mixture was monitored by TLC (using petroleum ether/AcOEt = 80:20 as an eluent).After completion of the reaction, the solid product was collected by filtration at pump and washed with methanol and water.The crude product was subjected to purification by recrystalization using ethanol, was subjected to further purification by silica gel column chromatography using 15% ethyl acetate, and 85% petroleum ether as an eluent to yield the β-amino carbonyl compounds.The structures of all the products were unambiguously established on the basis of their spectral analysis (IR, 1 H NMR and GC/ MS mass spectral data).All the products are known compounds.

Table 2 .
Optimization of various Lewis acids for the Mannich reaction a

Table 4 .
Effect of solvent on the synthesis of β-amino carbonyl ketones a *e-mail: kidwai.chemistry@gmail.comCerium Chloride (