key: cord-0777055-02g592st authors: Li, Qiao-Yan; Ge, Ze-Mei; Cheng, Tie-Ming; Li, Run-Tao title: An efficient three-component, one-pot synthesis of 2-alkylthio-4-amino-5-cyano-6-aryl(alkyl)pyrimidines in water date: 2012-06-28 journal: Mol Divers DOI: 10.1007/s11030-012-9376-z sha: 760c545acd958f605e34bd18d31fc41ce8dbb01c doc_id: 777055 cord_uid: 02g592st A convenient and practical method for the synthesis of 2-alkylthio-4-amino-5-cyano-6-aryl(alkyl)pyrimidines has been developed via a three-component, one-pot reaction from aldehydes, malononitrile and S-alkylisothiouronium salts in water at room temperature. A series of polysubstituted pyrimidines were prepared by this method in moderate to excellent yields. In addition, two kinds of pyrimidine-fused heterocyclic derivatives with potential pharmacological activity were constructed from our 2-alkylthio-4-amino-5-cyano-6-arylpyrimidines. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11030-012-9376-z) contains supplementary material, which is available to authorized users. Pyrimidine is an important heterocyclic scaffold that has attracted considerable attention in medicinal chemistry. Many pyrimidines and pyrimidine-fused heterocyclic derivatives have shown diverse biological activities, such as adenosine kinase inhibitors [1] , selective dihydrofolate reductase (from Mycobacterium tuberculosis and Plasmodium falciparum) inhibitors [2] [3] [4] , SecA inhibitors [5] , VEGF-R2 inhibitors [6] , SARS-CoV 3CL protease inhibitors [7] , HIV-1 [8] , adenosine receptor and growth hormone secretagogue receptor antagonists [9, 10] , and antimicrobial activity [11] [12] [13] . In addition to their pharmacological activities, some of them also exhibit interesting fluorescent properties [14] . Polyfunctional-substituted pyrimidines (PFSPs) play an important role in the preparation of substituted pyrimidine and pyrimidine-fused heterocyclic derivatives through the transformation of functional substituents on the pyrimidine scaffold. Therefore, many methods have been developed for the synthesis of PFSPs, and various substituted pyrimidine and pyrimidine-fused heterocyclic derivatives have been prepared from these PFSPs [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] 15 ]. 2-Alkylthio-4-amino-5-cyano-6-aryl(alkyl) pyrimidines represent one kind of the important PFSPs, and their pyrimidine and pyrimidine-fused heterocyclic derivatives were found to have special pharmacological activities. For example, derivatives of A exhibit topoisomerase II inhibitory activity against filarial parasite Setaria Cervi [16] , compounds B show DPP-IV inhibitory activity against type 2 diabetes [17, 18] , and compounds C display adenosine A2a receptor agonistic activity for treating glaucoma [19] . The pyrimidine-fused heterocyclic compounds D and E are PDK1 inhibitors and TLR modulators, respectively ( Fig. 1 ) [20] [21] [22] . To the best of our knowledge, there are mainly two methods for the synthesis of 2-alkylthio-4-amino-5-cyano-6aryl(alkyl)pyrimidines [23] [24] [25] [26] [27] [28] [29] , as shown in Scheme 1. Both require at least 2-3 synthetic steps using organic solvents under heating, which requires a tedious work-up, there is a limitation in reactant/substrates, and the method offers unsatisfactory yields. To alleviate all these drawbacks, a more efficient PFSPs synthesis is highly desirable. Multicomponent one-pot reaction represents an attractive alternative for the formation of multiple bonds in a single reaction giving access to complex molecules without the need of isolation or purification of reaction intermediates [30, 31] . In our continuing efforts to develop multicomponent one-pot synthesis of various heterocycles [32] [33] [34] , we here report an efficient synthesis of 2-alkylthio-4-amino-5cyano-6-aryl(alkyl)pyrimidine derivatives from the one-pot three-component condensation of aldehydes, malononitrile, and S-alkylisothiouronium salts in water. In our previous study, we developed an efficient synthesis of highly substituted pyridines via a three-component, onepot reaction of aldehydes, malononitrile, and S-alkyliso-thiouronium salts in water [32, 33] . Interestingly, we also obtained minor amounts of 2-alkylthio-4-amino-5-cyano-6-aryl(alkyl)pyrimidine as a byproduct in the above reaction. This discovery prompted us to explore the possibility of developing this side reaction into a more optimized method to synthesize 2-alkylthio-4-amino-5-cyano-6-aryl (alkyl)pyrimidines. We first studied the model reaction of benzaldehyde, malonoitrile, and S-methylisothiourea sulfate to optimize the reaction conditions and the results are listed in Table 1 . Referring to the reaction conditions in our previous study [32] [33] [34] , when equal amounts of each reactant were reacted in water at room temperature using sodium dodecyl sulfate (SDS) as the additive, we found that a strong base (e.g., NaOH) was unfa- vorable for the reaction (entry 1), organic amines (entries 2 and 3) worked better than weak inorganic bases (entries 4 and 5), and that using triethylamine as the base gave the best yield (entry 2, 50 % yield). The presence of SDS was not necessary in this reaction (entries 2 and 6). The stoichiometry of Et 3 N was essential and 4 equivalents of Et 3 N gave the best yield (entries 2, 7, 8). Increasing the reaction temperature decreased the yield significantly, which may be due to the decomposition of the intermediates at higher temperature (entries 13 and 14). Using organic solvents in the reaction did not increase yields (entries 9-12), due to poor solubility of the S-alkylisothiouronium salts. Fortunately, it was found that when the amount of aldehyde was increased slightly from 1 to 1.1 equivalent better yields were achieved (entries [14] [15] [16] [17] . Having optimized the reaction conditions for the model system (Table 1 , entry 15), we then proceeded to explore the scope and limitations of this three-component, one-pot reaction ( Table 2) . We first examined the influence of different aromatic heterocyclic aldehydes, with malononitrile and S-methylisothiouronium sulfate to give the corresponding 2-methylthio-4-amino-5-cyano-6-aryl(alkyl)pyrimidines in moderate to good yields (entries 1-17). The electronic property and position of the substituents on the aldehydes had an impact on the reaction. In general, substitution at 3-or 4-position with electron withdrawing groups was more favorable for the reaction than that at 3-or 4-position with electron donating groups, and substitution at 2-position was unfavorable for the reaction (entries 8, 10). Using acetaldehyde as an example of an aliphatic aldehyde was also examined, which afforded the desired product 3r in 35 % yield (entry 18). The scope of this method was further investigated through the reaction of pyridine-3-carboxaldehyde and malononitrile with various S-alkylisothiouronium salts under the same reaction conditions(entries [19] [20] [21] [22] [23] . The results showed that all reactions proceeded smoothly to afford the 2-alkylthio-4-amino-5-cyano-6-(3-pyridinyl)pyrimidines in 54-74 % yield. It is worth pointing out that due to the mild reaction conditions, this reaction can tolerate a wide range of functional groups, including nitro, amino, cyano, hydoxyl, methoxy, halide, and alkene. This advantage makes our method a very powerful tool for the synthesis of PFSPs, which could be transformed into structurally diverse substituted pyrimidines and pyrimidine-fused heterocyclic derivatives. Furthermore, this procedure does not require the separation and purification of intermediates and uses water as the reaction medium, which is environmentally friendly. To demonstrate the application of 2-alkylthio-4-amino-5cyano-6-(3-pyridinyl)pyrimidines in the synthesis of pyrimidine derivatives, we have successfully constructed two [20] [21] [22] . In summary, we have developed a convenient and practical method for the synthesis of 2-alkylthio-4-amino-5-cyano-6-aryl(alkyl) pyrimidines via a three-component, one-pot reaction of aldehyde with malononitrile and S-alkylisothiouronium salt in water at room temperature. The environmentally friendly reaction condition and a broad substrate scope will make this method widely applicable in the synthesis of structurally diverse pyrimidines and pyrimidine-fused heterocyclic derivatives. Melting point data were recorded on an X-4 micromelting point instrument and uncorrected. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance III 400 NMR spectrometer in CDCl 3 or DMSO-d 6 ( 1 H at 400 MHz and 13 C at 101 MHz) using tetramethylsilane (TMS) as internal standard. HRMS were recorded on Bruker Apex IV FTMS. IR were recorded using NEXUS-470 FTIR (Nicolet). Column chromatography was performed on silica gel (zcx.II; 200-300 mesh). All reagents were purchased from commercial suppliers and used without further purification. Tetrahydrofuran was dried over sodium. General procedure for the synthesis of 3a-3w Malononitrile (1 mmol) and S-alkylisothiouronium salt (2 mmol) were dissolved in 20 mL water and then the aldehyde (1.1 mmol) and Et 3 N (4 mmol) were added. The mixture was stirred at room temperature for 6-24 h. The endpoint of the reaction was monitored by TLC. The resulting mixture was extracted with ethyl acetate (1 × 10 mL), and the combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo. Purification of the resulting residue by column chromatography (petroleum ether/EtOAc, 8:1-6:1, v/v) afforded the desired products 3a-3o and 3r-3w. To get the products 3p and 3q, at the end of the reaction the resulting mixture were filtered, and the precipitates were dried and recrystallized (EtOAc/MeOH, 1:1, v/v). In cases where the reactant aldehyde is solid, a minor amount of ethyl acetate was used to first dissolve it before its addition. Obtained Obtained in 54 % yield; yellow power crystal; mp 187- Compound 3j (2 mmol) was dissolved in 20 mL anhydrous THF at room temperature. Lithium aluminum hydride (8 mmol) in 5 mL anhydrous THF was then added slowly, and the mixture was stirred at room temperature for 6 h before the dropwise addition of 10 mL of water at 0 • C. Afterwards, 3 mL 3N hydrochloric acid was added, and the mixture was extracted with ethyl acetate (2 ×20 mL). The solid of sodium hydroxide was added to the aqueous layer to reach pH 11, and then the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in 20 mL DMF, and CuI (0.1 equiv), l-proline (0.2 equiv) and Cs 2 CO 3 (2 equiv) were added into the solution under nitrogen atmosphere. The mixture was stirred at room temperature for 30 min, then heated at 100 • C for 24 h in an oil bath. The resulting suspension was allowed to cool to room temperature and filtered. The precipitate was washed with ethyl acetate (10 mL) and 30 mL of water were added to the filtrate. The filtrate was then extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc/petrol, 2:1, v/v) to give compound D as the product. Pyrimido [5,4-c] quinoline-2-methylthio-4,5-diamine (E) Compound 3h (2 mmol) and SnCl 2 · H 2 O (4 mmol) were dissolved in 20 mL 1N hydrochloric acid in a flask. The solution was heated at 100 • C for 48 h in an oil bath. The resulting suspension was allowed to cool to room temperature and filtered. The precipitate was washed with water and dried to afford compound E as yellow powder in 85 % yield; mp > 300 Amino-5-cyano-2-methylthio-6-(3-methoxyphenyl Obtained in 60 % yield 82 (s, 3H), 2.51 (s, 3H); 13 C NMR (101 MHz Obtained in 77 % yield; white needle crystal 51 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 174 Amino-5-cyano-2-methylthio-6-(3-pyridineyl Obtained in 82 % yield; white needle crystal Amino-5-cyano-2-methylthio-6-(4-pyridineyl 52 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) Obtained in 35 % yield CDCl 3 ) δ 5.52 (s, 1H), 2.56 (s, 3H), 2.55 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) Obtained in 63 % yield; white needle crystal; mp 172-173 • C (EtOAc/petrol) KBr) ν 3389, 3053, 2213, 1642, 1537 cm −1 ; 1 H NMR (400 MHz Hz, 1H), 8.81-8.75 (m, 1H), 8.31 (d, J = 7.9 Hz, 1H), 7.46 (dt,J = 7.4, 3.8 Hz, 1H) Obtained in 58 % yield; white needle crystal; mp 159-162 • C (EtOAc/petrol) CDCl 3 ) δ 9.18 (s, 1H), 8.77 (d, J = 4.7 Hz, 1H), 8.26 (d, J = 7.7 Hz, 1H), 7.46-7.29 (m, 6H) Obtained in 56 % yield; white needle crystal; mp 197-199 • C (EtOAc/petrol) CDCl 3 ) δ 9.22 (s, 1H), 8.77 (d, J = 4.7 Hz, 1H) 4-Amino-5-aryl-6-arylethynylprimidines: structure-activity relationships of non nucleoside adenosine kinase inhibitors Structure-based design, synthesis and preliminary evaluation of selective inhibitors of dihydrofolate reductase from Mycobacterium tuberculosis Development of 2,4-diaminopyrimidines as antimalarials based on inhibition of the S108N and C59R+S108N mutants of dihydrofolate reductase from pyrimethamine-resistant Plasmodium falciparum Inhibitors of multiple mutants of Plasmodium falciparum dihydrofolate reductase and their antimalarial activities The first low µM SecA inhibitors 4-Aryl-5-cyano-2-aminopyrimidines as VEGF-R2 inhibitors: synthesis and biological evaluation Synthesis, docking studies, and evaluation of pyrimidines as inhibitors of SARS-CoV 3CL protease Pyrimidine thioethers: a novel class of HIV-1 reverse transcriptase inhibitors with activity against BHAP-Resistant HIV A new generation of adenosine receptor antagonists: from di-to trisubstituted aminopyrimidines ) 2,4-Diaminopyrimidine derivatives as potent growth hormone secretagogue receptor antagonists Chloropyrimidines as a new class of antimicrobial agents Synthesis and antiinflammatory activity of 4-amino-2-aryl-5-cyano-6-{3-and 4 A novel and efficient one step synthesis of 2-amino-5-cyano-6-hydroxy-4-arylpyrimidines and their anti-bacterial activity Pyrimidine-core extended π -systems: general synthesis and interesting fluorescent properties Novel benzimidazole-pyrimidine conjugates as potent antitumor agents Synthesis of 4-amino-5-cyano-2,6-disubstituted pyrimidines as a potential antifilarial DNA topoisomerase II inhibitors Aminomethylpyrimidines as novel DPP-IV inhibitors: a 10 5 -fold activity increase by optimization of aromatic substituents An aminomethylpyrimidine DPP-IV inhibitor with improved properties Discovery of dibenzo[c,f][2,7]naphthyridines as potent and selective 3-phosphoinositide-dependent kinase-1 inhibitors Pyrimido[5,4-c]quinoline-2,4-diamine derivatives and methods of use thereof. US Patent Preparation of benzonaphthyridines as TLR activity modulators Abdel-Motty F (1989) Reactions with 2-(methylthio)pyrimidines. Synthesis of some new fused pyrimidines 2-Mercaptopyrimidines from 4H-pyrans: novel syntheses of triazolo[4,3-a]pyrimidines Synthesis and antimicrobial activity of thioxopyrimidines and related derivatives Reactions of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b] thiophene and 2-amino-3-cyano-4, 7-diphenyl-5-methyl-4H-pyrano[2,3-c]pyrazole with phenylisocyanate, carbon disulfide, andthiourea Reactions with substituted acrylonitriles: a novel synthesis of polysubstituted pyrimidines Synthesis of some new pyrimidine and fused pyrimidine derivatives (part 2) Asymmetric organocatalytic domino reactions Multicomponent domino reactions for the synthesis of biologically active natural products and drugs Anefficent four-compent, one-pot synthesis of poly-substituted pyrimidines in water Synthesis of highly substituted pyridines via a one-pot, three-component cascade reaction of malononitrile with aldehydes and S-alkylisothiouronium salts in water Thia-Michael addition using cheap and odorless S-alkylisothiouronium salts as thiol equivalents in water Acknowledgments The project is supported by NSFC (No. 21172011).