Green and Selective Synthesis of N-Substituted Amides using Water Soluble Porphyrazinato Copper ( II ) Catalyst

N,N’,N’’,N’’’-Tetrametil tetra(2,3-piridil)porfirazinato metil sulfato de cobre(II) ([Cu(2,3-tmtppa)](MeSO4)4) catalisou com sucesso a conversão direta de nitrilas a amidas N-substituídas. A síntese seletiva do tipo one pot de amidas N-substituídas a partir de nitrilas e aminas primárias foi realizada em refluxo de água. O catalisador foi recuperado e reusado no mínimo 4 vezes, mantendo a sua eficiência.


Introduction
Amide bond formation is a fundamental reaction of great interest in organic and bioorganic chemistry, peptides and proteins include these bonds.2][3][4][5] Current popular synthesis strategies of amides are the reaction of amines with carboxylic acids, transamidation of amides with amines, or with the reaction of carboxylic acid derivatives such as acyl halides, anhydrides, esters and other activated species usually in the presence of coupling reagents.  Reaions promoted by coupling reagents are fundamental in organic synthesis.The majority of amide bond syntheses is merely stoichiometric, making these methods generally expensive and wasteful procedures. 28As the society needs forward-looking environmentally acceptable technology, the development of catalytic reactions that use transition-metal complex catalysts under neutral and mild reaction conditions is particularly important.These criteria include atom efficiency, formation of little inorganic waste, and selective synthesis of desired products, encouraging an effort towards using environmentally friendly catalytic processes that will not produce such waste.][57][58][59][60][61] A little-known reaction which yields amides is the hydrolytic amidation of nitriles with amines.A platinum and an iron catalysts were found to perform the coupling. 53,54Nitriles can also be coupled with alcohols to form amides in the Ritter reaction.As an alternative to sulfuric acid, the Ritter reaction can be catalyzed by metal complexes such as bismuth triflate 62 and iron complexes. 63][66] In the course of our present study, our interesting is in using [Cu(2,3-tmtppa)](MeSO 4 ) 4 (Scheme 1) as a safe, environmentally benign and efficient acid catalyst in the preparation of N-substituted amides.

General
The products were purified by column chromatography.The purity determinations of the products were accomplished by thin layer chromatography (TLC) on silica gel polygram STL G/UV 254 plates.The melting points of the products were determined with an Electrothermal type 9100 melting point apparatus.The Fourier transform infrared (FTIR) spectra were recorded on an Avatar 370 FTIR Therma Nicolet spectrometer.The nuclear magnetic resonance (NMR) spectra were provided on Brucker Avance 100 and 400 MHz instruments in CDCl 3 .Elemental analyses were performed using an Elementar Vario EL V5. 19.1121 and Thermofinnigan Flash EA 1112 Series instruments.Mass spectra (MS) were recorded with a Shimadzu GC-MS-QP5050 and CH7A Varianmat Bremem instruments at 70 eV.The known products were characterized by FTIR and 1 H NMR spectra and comparisons of their melting points (or those of the derivatives) were done with authentic samples.[69]

Results and Discussion
The optimization of the reaction conditions was carried out for the reaction of phenylacetonitrile with benzylamine in the presence of [Cu(2,3-tmtppa)](MeSO 4 ) 4 under various reaction parameters in order to achieve the maximum chemical yield at the lowest reaction time and lowest reaction temperature.The general reaction is outlined in Scheme 2 and the representative results are shown in Table 1.
In the absence of any catalyst, there was no conversion to N-benzyl-2-phenylacetamide (Table 1, entries 1, 20 and 21).In solvent free condition and applying different molar ratios of phenylacetonitrile, benzylamine, [Cu(2,3-tmtppa)] 4+ was identified as a catalyst for N-benzyl-2-phenylacetamide formation but in prolonged reaction time and low yield (Table 1, entries 2-5).In an effort to develop better reaction conditions, different solvents were screened for the preparation of N-benzyl-2-phenylacetamide from the reaction of phenylacetonitrile with benzylamine in the presence of 0.  1, entry 18).To investigate the effect of catalyst loading, the formation of N-benzyl-2-phenylacetamide was carried out in refluxing H 2 O in the presence of 1 mol% of catalyst.According to this study, increasing the catalyst loading did not lead to higher conversion (Table 1, entry 24).It is noteworthy that no evidence for reaction of phenylacetonitrile with water was observed in the absence of benzylamine and any tendency between phenylacetonitrile and H 2 O can be prohibited (Table 1, entry 27).
To explore the generality and scope of the N-substituted amides formation catalyzed by [Cu(2,3-tmtppa)](MeSO 4 ) 4 , the optimized reaction conditions (1:2 molar ratio of nitrile:amine, 0.5 mol% catalyst, refluxing H 2 O) were used for the synthesis of a series of amide derivatives (Table 2).
According to the results obtained (Table 2), N-substituted amides were prepared from the reaction of aromatic and aliphatic nitriles with primary aliphatic amines in the presence of [Cu(2,3-tmtppa)](MeSO 4 ) 4 in high isolated yields.The mechanism of this transformation is unclear.On the basis of proposed mechanism in Scheme 3, the catalytic activity of [Cu(2,3-tmtppa)](MeSO 4 ) 4 could well be attributed to the Lewis acidity of the complex.The catalytic reaction of alkyl and aryl nitriles with primary amines was achieved by refluxing aqueous solution of the corresponding nitriles, in the presence of 0.5 mol% [Cu(2,3-tmtppa)](MeSO 4 ) 4 , which initially generates the nitrile bound copper species I.This idea is supported by performing the reaction in the absence of catalyst.Without any catalyst, the reaction is not completed even after long period of time ( The reaction was performed in the absence of catalyst; b the reaction was performed in the presence of 1 mol% of catalyst.
Cu II Scheme 3. A proposed mechanism for the formation of N-substituted amides.
secondary amines and aryl amines.Surprisingly, even after long period of time, secondary amines and aryl amines remain intact in the reaction medium.Vol.00, No. 00, 2013 [Cu(2,3-tmtppa)](MeSO 4 ) 4 acts as a recyclable catalyst for one pot amide formation from various nitriles and primary amines in refluxing H 2 O, which provides a new and green catalytic system for N-substituted amide synthesis.The catalyst can be easily recovered from the reaction mixture by extraction of organic compounds (3 × 5 mL CH 2 Cl 2 ).The aqueous layer was evaporated and the catalyst was washed with CH 2 Cl 2 three times to remove the products followed by drying in air at room temperature.Using this treatment, the recyclabilty of the catalsyt was evaluated for the reaction of phenylacetonitrile with benzyl amine (Table 3).The recovered catalyst was reused at least four times without any decrease in the yield of the N-benzyl-2-phenylacetamide.The 5 th run gave 95% conversion after 19 h, but complete conversion and similar yield was obtained after 25 h.
The results obtained (Table 2) clearly demonstrate that this method is inapplicable to synthesis of primary and N,N-disubstituted amides.The catalytic activity of [Cu(2,3-tmtppa)](MeSO 4 ) 4 in this reaction is selective.
In our experiments, the completion of the reaction was confirmed by the disappearance of the nitrile on TLC followed by the disappearance of CN stretching frequency at 2230 cm -1 in the FTIR spectra.Also, absorption bands at 1677-1612 and 3396-3284 cm -1 due to carbonyl and NH group of N-substituted amide in FTIR spectra confirmed the amide formation.In the 1 H NMR spectrum, the NH proton of N-substituted amide showed a downfield shift as compared to the NH 2 protons of amine.In the 13 C NMR spectrum, a signal at 173-161 ppm is assigned to the quaternary carbonyl carbon.The structure of all products was further confirmed by mass spectroscopy and CHN analysis.
5 mol% of [Cu(2,3-tmtppa)](MeSO 4 ) 4 .No product was obtained when the reaction was performed in dimethyl sulfoxide (DMSO), dimethylformamide (DMF), CH 2 Cl 2 and Et 2 O (Table 1, entries 6-9).The catalytic effect of [Cu(2,3-tmtppa)](MeSO 4 ) 4 was efficiently decreased in aprotic polar solvents such as DMSO and DMF because of the strong coordination of solvent with Cu II .As shown in Table 1, when the reaction was performed in refluxing 1,4-dioxane and H 2 O, N-benzyl-2-phenylacetamide was obtained in good to excellent yields.To improve amide formation, the effect of different molar ratios of phenylacetonitrile, benzylamine was examined in 1,4-dioxane and H 2 O (Table 1, entries 10-19).Also, the effect of temperature was studied in 1,4-dioxane and H 2 O.No conversion was observed when the reaction was carried out at room temperature (Table 1, entries 22-23).It seems that the temperature is an important factor in the preparation of N-benzyl-2-phenylacetamide.The best results were obtained in 1,4-dioxane, H 2 O, toluene and tetrahydrofuran (THF) (Table 1, entries 10-19,25-26).Because of safety, economic and handling considerations, H 2 O was chosen for further experiments.Maximum yield was observed in refluxing H 2 O with a 1:2 molar ratio of phenylacetonitrile:benzylamine (Table

Table 1
2O can be prohibited).Copper complex III produces N-substituted amide with concomitant loss of an ammonia molecule.Finally, the regeneration of catalyst initiates a second catalytic cycle.Nevertheless, at this time, there is no experimental evidence for I, II and III formation and action in this manner.However, further

Table 2 .
continuation mechanistic studies are required to confirm this mechanism.The catalytic activity of [Cu(2,3-tmtppa)](MeSO 4 ) 4 was examined for the reaction of alkyl and aryl nitriles with

Table 3 .
Reaction of phenylacetonitrile with benzylamine in the presence of reused catalyst aThe second numbers in the third column correspond to yields after 19 h.