Chinese Chemical Letters  2015, Vol.26 Issue (01):152-156   PDF    
Synthesis of N2-arylaminopyrimidine-5-carbonitrile derivatives via SNAr amination reaction
Shahnaz Rostamizadeha , Masoomeh Nojavana, Reza Aryanb    
a Department of Chemistry, Faculty of Science, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran;
b Department of Chemistry, Faculty of Science, University of Zabol, Zabol, Iran
Abstract: An efficient and high-yielding synthesis of N2-arylaminopyrimidine-5-carbonitrile derivatives starting from arylamines and 2-methylthio-pyrimidine-5-carbonitrile derivatives has been developed in the presence of cesium carbonate as basic reagent. This new protocol showed high chemical tolerance for a range of functional groups, and only the methylthio substituent on C2 of the pyrimidine ring was replaced with arylamine derivatives under the reaction conditions.
Key words: N2-Arylaminopyrimidine-5-carbonitrile     derivatives     Pyrimidine-5-carbonitrile derivatives     C-N bond formation     SNAr mechanism    
1. Introduction

The N2 -arylaminopyrimidines exhibit interesting pharmaceutical and agrochemical properties. This structural motif can be found in a variety of biologically active compounds,such as anticancer trademark agents,Pazopanib (VotrienTM ) and Imitanib (GleevecTM ) [1, 2, 3, 4],Fungicides [5] and anti-HIV agents,such as IntelenceTM [6, 7] (Fig. 1).

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Fig. 1. Biologically active compounds withN2 -arylaminopyrimidine building block

Because of the occurrence of aryl C-N bond in pharmaceuticals and natural products,its synthesis has gained a broad attention in the field of synthetic organic chemistry,leading to expanding application in many total syntheses and the industrial preparation of numerous pharmaceuticals [8, 9, 10, 11, 12]. A few approaches have been reported for the synthesis of carbon-nitrogen bonds on the aromatic ringsviathe reaction of amines with leaving groups such as the alkylthio group. These procedures are classified into two different sets of reactions: The oxidation of alkylthio to sulfone prior to using amines as nucleophiles [13, 14] and the direct nucleophilic replacement of alkyl- and arylthio groups [15, 16, 17, 18, 19]. Recently,application of transition metal-catalyzed amination of aryl halides in processes such as Goldberg and Buchwald-Hartwig cross-coupling reactions were also developed for this purpose [8, 20, 21, 22, 23]. In addition,Pd- or Cu-catalyzed coupling reactions between heteroaryl thioethers and amines have also been reported as milder alternatives [24]. However,the use of toxic and expensive transition metals is a significant limiting factor for these processes and under Goldberg and Buchwald-Hartwig amination conditions. 4-Amino-6-(4-chlorophenyl)-2-methylthiopyrimidine-5-carbonitrile 1b reacts at both the methylthio group at the C2 of starting pyrimidine ring and 4-chlorophenyl ring on the C6 leading to substitution products 2-4(Scheme 1).

With a view of the above-mentioned considerations and in continuation of our previous work for the synthesis of 4-amino-6-aryl-2-methylthio-pyrimidine-5-carbonitrile derivatives [25],we were encouraged to introduce a novel transition metal-free protocol for the synthesis of new derivatives of 2-arylaminopyrimidine through the amination of 4-amino-6-aryl-2-methylthiopyrimidine-5-carbonitrile derivatives (Scheme 1).

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Scheme 1.Synthesis ofN2 -arylaminopyrimidine-5-carbonitrile derivatives under SNAr reaction condition and Goldberg and Buchwald-Hartwig amination condition.

To address this purpose,new synthetic strategies are needed to be developed that would enable the facile synthesis of N2 -arylaminopyrimidines. Herein,we wish to describe a successful strategy by which the desired product2can be achieved solely with high yields under the SNAr reaction conditions,and the possibility for the formation of side products would be excluded. 2. Experimental

Melting points were recorded on a Buchi B-540 apparatus. IR spectra were recorded on an ABB Bomem Model FTLA200-100 2.1. General procedure for the synthesis of 4-amino-6-aryl-2-mthylthio pyrimidine-5-carbonitrile1

Malononitrile (1 mmol),aldehyde (1 mmol),S-methylisothiouronium iodide (1 mmol),and nanocatalyst MCM-41-NH2 (0.06 g) were ground and placed in a test tube. The reaction was then stirred under heating for 1 h at 808C and monitored by TLC (EtOAc:petroleum ether = 1:2). After completion of the reaction, the reaction mixture was cooled to room temperature and added EtOAc,and then the mixture was stirred for at least 10 min. The reaction mixture was filtered off to remove the catalyst and evaporatedin vacuo to obtain a solid product. The residues were further purified by crystallization from EtOH [25]. 2.2. General procedure for the synthesis of2a-2h

A mixture of 4-amino-6-aryl-2-mthylthiopyrimidine-5-carbonitrile 1 (1 mmol),arylamine (1.2 mmol),cesium carbonate (1 mmol,0.32 g) in 5 mL DMF was heated at 120℃ and monitored instrument. 1H NMR and 13C NMR spectra were measured on a Bruker DRX-300 spectrometer at 300 MHz and 75 MHz using TMS as an internal standard. Chemical shifts (d) were reported relative to TMS,and coupling constants (J) were reported in hertz (Hz). Mass spectra were recorded on a Shimadzu QP 1100 EX mass spectrometer with 70 eV ionization potential. Elemental analyses of new compounds were performed with a Vario EL III 0 Serial No. 11024054 instrument and their results favorably agreed with the calculated values. by TLC (AcOEt:petroleum ether = 1:2). After completion of the reaction,the reaction mixture was cooled to ambient temperature, neutralized with 10% (v/v) HCl solution (20 mL) and was extracted by ethyl acetate (20 mL×3). The combined organic layers were dried over Na2SO4 and concentratedin vacuo. The solid residues were further purified by crystallization from EtOH to furnish the desiredN2 -arylaminopyrimidine-5-carbonitrile product.

4-Amino-6-(4-chlorophenyl)-2-(phenylamino)pyrimidine-5-carbonitrile (2b): Pale yellow powder; mp: 268-270℃; IR (KBr,cm -1 ): υ3471,3332,3229,2217,1647,1534; 1H NMR (300 MHz,DMSO-d6): d7.82-7.85 (m,2 H),7.62-7.72 (m,3H), 7.06-7.09 (d,2H,J= 8.6 Hz),6.64-6.67 (d,2H,J= 8.6 Hz); 13C NMR (75 MHz,DMSO-d6): δ174.4,168.9,168.0,166.3,135.9,131.2, 130.2,128.8,128.6,116.1,115.8,111.1,81.1; MS m/z: 321(87,M+ ), 320(100),118(37),77(22),51(9); Anal. Calcd. for C17H12ClN5:C, 63.46; H,3.76; Cl,11.02; N,21.77. Found: C,63.61; H,3.79; N, 21.58.

4-Amino-6-(4-chlorophenyl)-2-((3,4-dimethylphenyl)amino)-pyrimidine-5-carbonitrile (2e): Pale yellow powder; mp: 256℃; IR (KBr,cm -1 ): υ3442,3338,3214,2218,1642,1558; 1H NMR (300 MHz,DMSO-d6): δ 9.66 (s,1H,NH),7.82-7.85 (d,2H, J= 8.3 Hz),7.59-7.62 (d,3H,J= 8.3 Hz),7.48-7.51 (d,1H, J= 7.3 Hz),6.99-7.02 (d,1H,J= 8.2 Hz),2.18 (s,3H,CH3),2.15 (s,3H,CH3); 13C NMR (75 MHz,DMSO-d6):δ167.4,164.6,160.1, 140.9,137.3,135.9,130.6,130.1,129.4,120.8,119.0,117.6,116.0, 112.5,66.3,19.6,18.7; MS m/z: 247(29),198(38),139(100), 111(52),75(49),50(22); Anal. Calcd. for C19H16ClN5: C,65.24; H, 4.61; Cl,10.13; N,20.02. Found: C,65.53; H,4.72; N,19.79. 3. Results and discussion

Initially,in order to obtain the desired product 2,the reaction of 4-amino-6-(4-chlorophenyl)-2-methylthio-pyrimidine-5-carbonitrile 1b (1 mmol),with 1.2 mmol of 4-chloroaniline was investigated in different solvents and in the presence of various bases,ligands and catalysts (Scheme 2,Table 1).

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Scheme 2.Model reaction used for the synthesis ofN2 -arylaminopyrimidine-5-carbonitrile derivatives.

Table 1
Screening the effect of different solvents and various bases in the reaction of 4-amino-6-(4-chlorophenyl)-2-methylthiopyrimidine-5-carbonitrile and aniline for the formation of product2c

The best results were obtained using cesium carbonate in DMF as solvent at 1208C without using any ligands (Table 1,entry 14). The reaction in Scheme 2 was also studied under different amount of cesium carbonate,and the best results were obtained using 0.32 g (1 mmol,equimolar to the reactants) of cesium carbonate. Increasing the amount of base did not affect the reaction time and yield but decreased amounts of cesium carbonate lead to prolonged reaction times (up to 12 h) and lower yields of the products. The reaction conditions used in the present work are very similar (in terms of reaction times,amount of base,and temperature) to transition metal catalyzed processes.

To explore the scope and generality of this reaction,we repeated this process for various substituted 2-methylthiopyrimidine-5-carbonitrils and arylamine derivatives,in the presence of cesium carbonate in DMF as solvent (Scheme 3). The reaction proceeded efficiently with various substituted 2-methylthiopyrimidine-5-carbonitrile derivatives (Table 2).

As indicated in Table 2,when the pyrimidine derivatives with electron releasing groups or bulky substituent on aryl ring at C6 position were used,the reaction did not proceed at all (entries 9- 11,Table 2). The case of no product formation when Me and OMe substituents are placed on 6-aryl ring can be explained by comparing the Hammett substituent constants for methyl, methoxy (entries 9 and 10,Table 2) with chlorine (entry 3, Table 2). ThesPfor methyl,methoxy and Cl are-0.17,-0.27 and 0.23 respectively. This implies that because of electron-donating character of methyl and methoxy (negative values forsP) the six aryl and pyrimidine rings are consequently more electron-rich to be attacked by aniline derivatives. Instead,the chlorine atom withdraws electrons from the aryl ring leading to consecutive electron deficiency in pyrimidine ring and facilitates the nucleophilic attack by aniline derivative. Also,4-nitroaniline did not react with reactive electron-poor pyrimidine derivatives because of the sP constant for NO2 which equals to 0.78 (intensively electronwithdrawing) (entries 12-15,Table 2).

Table 2
Synthesis ofN2 -arylaminopyrimidine-5-carbonitrile derivatives using cesium carbonate in DMF as solvent at 120℃

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Scheme 3.Synthesis ofN2 -arylaminopyrimidine-5-carbonitrile derivatives under optimized reaction conditions

A SNAr (addition-elimination) mechanism under basic condition is shown for the formation of N2 -arylaminopyrimidine-5-carbonitrile derivatives 2 in Scheme 4. First,anionic arylamine generated by cesium carbonate as base,attacks the C2 of pyrimidine ring as a nucleophile. Then,the resulting stable Meisenheimer complex releases thiolate anion as leaving group and transforms to the desired product 2 through aromatization (Scheme 4) [26, 27]. The use of heavier alkali metal carbonates such as cesium carbonate seemed to provide advantages over the other members of this class of compounds in terms of yield and the reaction rate as previously reported [28].

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Scheme 4.The SNAr mechanism for the formation ofN2 -arylaminopyrimidine-5-carbonitrile derivatives2
4. Conclusion

In conclusion,we have demonstrated the new procedure for the preparation ofN2 -arylaminopyrimidine-5-carbonitrile derivatives through the substitution of the methylthio group with arylamines. Unlike the metal catalyzed substitution reaction,no substitution of halide atom took place at the aryl group on C6 position as a side reaction. The reaction provides the easy access to the synthesis of interestingN2 -aryl pyrimidine-5-carbonitrile heterocycles in good to excellent yields of the products. Relatively short reaction times and milder reaction temperature are the other advantages of the present method in comparison to the previous reports. Finally,it should be pointed out that the reaction seems to follow a pathway in which a Meisenheimer complex is involved.

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