Microwave-assisted simple synthesis of 2-anilinopyrimidines by the reaction of 2-chloro-4,6-dimethylpyrimidine with aniline derivatives

A series of 2-anilinopyrimidines including novel derivatives has been obtained from 2-chloro-4,6-dimethylpyrimidine by aromatic nucleophilic substitution with differently substituted anilines under microwave conditions. The substituents had a significant impact on the course and efficiency of the reaction. The results reported herein demonstrate the efficacy of microwaves in the synthesis of the title heterocyclic compounds as compared to the results obtained with conventional heating. The 2-anilinopyrimidines described are of potential bioactivity.


Introduction
The biological activity of anilinopyrimidines as fungicides and pesticides is well-known and widely reported. [1][2][3][4][5][6][7] Recently, a few 2-anilinopyrimidine derivatives have been evaluated as kinase inhibitors having antiproliferative activity against cancer cell lines. [8][9][10][11] The role of this class of compounds in the generation of supramolecular networks for molecular recognition has also been demonstrated. 12 Different methods have been proposed to synthesize anilinopyrimidines: (a) the cyclization between guanidines (generally obtained from isothiourea salts and alkyl(aryl)amines in the presence of strong bases) and b-diketones, ethyl acetoacetate or ethyl cyanoacetate under reuxing for several hours (b) the transition metal-free cross-coupling reactions, (c) the aromatic nucleophilic substitution of halogen pyrimidines or substituted heterocycles having an alkylsulfonyl group with anilines. [13][14][15][16] In particular, the substitution of the halogen atom in 2-aminopyrimidines by alkyl-or arylamines occurs under acidic conditions. 17,18 The main disadvantage of these procedures is the requirement for drastic conditions and long reaction times.
In the last years a large number of heterocyclic compounds including anilinopyrimidines has been synthesized by microwave (MW) irradiation. [19][20][21] The main advantage of the use of this technique is the decrease of the reaction time from several hours to a few minutes or seconds in comparison to the results obtained on conventional heating. 22,23 Moreover, less byproducts are formed in MW-assisted reactions. 24 However, in most cases, it is not possible to predict if a given reaction will be improved under MWs or not. 25 At the same time, if the energetics of the target reaction is known, it is possible to judge in advance about the appropriateness of the application of MWs. The ideal subject of MW-promoted reactions are those that have a relatively high enthalpy of activation, and are thermoneutral. [26][27][28] In this article we describe the simple synthesis of a series of anilinopyrimidine derivatives including three new compounds by the reaction of 2-chloro-4,6-dimethylpyrimidine with substituted anilines under MW irradiation. This method represents a novel approach to the synthesis of the target compounds, and allows high yields in eco-friendly conditions. Recently, some green and recyclable reaction media have been proposed, such as water, PEG-200, and 2-methyltetrahydrofuran. [29][30][31] The use of ethanol, one of the environmentally preferable solvents, confers the eco-friendly character to the synthesis of the investigated compounds. [32][33][34]

Results and discussion
Recently, it has been demonstrated that acid catalysis promoted the reaction of chloro-N-heterocycles with anilines. 19,35 The reaction between 2-chloro-4,6-dimethylpyrimidine and substituted anilines in ethanol at 160 C under MW irradiation for 10 min, is an aromatic nucleophilic substitution taking place via the corresponding Meisenheimer complexes, and affording 2-anilinopyrimidines. An aminopyrimidine from benzylamine has also been synthesized as shown in Scheme 1.
In order to verify the role of MWs in the investigated reactions, compound (1) was also synthesized on conventional heating at reux for 72 h. Aer the work-up described in the general procedure, product (1) was isolated in a yield of 68% that is signicantly lower than that obtained by MW irradiation (90%). It has been demonstrated that in the MW-assisted synthesis, the polarity and polarizability of the reagents, transition states and intermediates may inuence the absorption of MWs and hence the heating. 37 The presence of substituents, their electronic effects and their position in the aromatic ring may inuence the properties of the compounds, and the rate of their reactions. [38][39][40][41][42][43] In the investigated S N Ar reactions, the electron-donating effect (+I) of the alkyl group increases the nucleophilic nature of the amino group of the aniline moiety, as it was demonstrated by the high yields obtained for compounds (5) and (16) due to the presence of the CH 3 group in the para or ortho position, respectively Scheme 1 MW-assisted synthesis of the compounds (1-17). Scheme 2 MW-assisted synthesis of bis-derivative (18).
( Table 1). A similar effect was observed in the phenyl substituted instance (11). In case of products (3) and (4), the high yields of 90 and 92%, respectively, are the consequence of the electronreleasing MeO and HO groups. These substituents can promote the reactivity of the aniline molecule because of the major +M effect versus the ÀI effect. On the other hand, regarding compound (10), in which the nitro group posseses an ÀM effect, nucleophilicity of the amino group is decreased, as it was demonstrated by the lower yield of 39%.
Compounds (1), (2) and (3) are well-known molecules: heterocycle (1) has been recently patented for its antimitotic activity as a topical formulation against psoriasis, 44 while derivatives (2) and (3) are commercial fungicides pyrimethanil and andoprim, respectively. 2,45,46 In this work, these species and their analogues have been synthesized in a one pot reaction instead of the guanidine route. 14 To the best of our knowledge, compounds (11), (12) and (18) are reported for the rst time.

Conclusions
MW irradiation allowed rapid and high yield "green" synthesis of a series of 2-anilinopyrimidines. In this work, 18 products were prepared, including new compounds (11), (12) and (18) and the benzylamine derivative (17). The electronic effect of the substituents had an impact on the outcome of the reaction by inuencing the nucleophilic character of the amino group of the aniline molecule. As N-heterocycle-based molecules are important due to their applicability in medicinal chemistry, 47 the compounds synthesized beyond the antimitotic (1) and fungicidal (2) and (3) may also posses bioactive properties.

Material and methods
All the reagents, were purchased from commercial suppliers and employed without further purication. Reactions were monitored by thin layer chromatography (TLC) on silica gel plates (60 F254) that were visualized under UV light (254 nm). The silica gel (Kieselgel 4 , 0.04-0.063 mm) used in the column chromatography was purchased from Merck. The MW-assisted reactions were performed using a Biotage Initiator Plus oven. Infrared absorption spectra were recorded on a Varian 1000 Fourier-transform infrared spectrometer. The 1 H and 13 C-NMR spectra were recorded on a Varian-Mercury 300 spectrometer, operating at a frequency of 300 MHz and 75 MHz, respectively. Melting points were determined on a Büchi B-540 apparatus and are uncorrected. Electrospray high-resolution MS measurements were performed on a Thermo Velos Pro Orbitrap Elite Hybrid Mass spectrometer (Thermo Fisher Scientic, Bremen, Germany). The ionization method was ESI and operated in positive ion mode. The capillary temperature was set at 275 C. Samples were infused into the ESI source MeOH solutions at a ow rate of 3 mL min À1 . Resolving power of 60 000 (FWHM) at m/z 400. Data acquisition and analysis were accomplished with Xcalibur soware version 3.0 (Thermo Fisher Scientic Inc.).