Microwave assisted solventless synthesis of melamines with flexible aromatic substituents

A fast, highly efficient and environmentally friendly solvent-free procedure under microwave irradiation, using silica gel supported reagents for the synthesis of melamines with flexible aromatic N -substituents is developed. It is shown that both microwaves and silica gel accelerate the transformation studied. The synthetic approach presented herein has several advantages. It is a low cost protocol as using the cheap and easily available starting material, cyanuric chloride. The conversion is complete within 3 min, which leads to a serious energy saving. Hydrogen chloride is the only by-product, which makes the procedure an atom economy benign. This by-product is quenched as ammonium salts during the reaction, thus preventing its release into the environment.

An efficient atom economy and environmentally friendly solvent-free protocol for the synthesis of a series of melamines with flexible aromatic N-substituents under microwave irradiation is presented herein.

Results and Discussion
The starting 2-chloro-4,6-dimorpholino-1,3,5-triazine (2) and 2,4-dichloro-6-morpholino-1,3,5triazine (10) were prepared by replacing the chlorine atoms in cyanuric chloride with morpholine, according to a known procedure. 69,70Morpholine was chosen as a non-aromatic amine due to the observed anti-inflammatory activity of similar melamines, 35 which are described by the authors as "an aspirin of the 21 st century".The disubstituted product 2 was easily obtained by using morpholine both as a reagent and as a base, while in the case of 10 equimolar amounts of morpholine and carbonate as a base were used at 0 o C to achieve the monosubstitution selectively.The target melamines were afterward obtained in a solventless protocol under microwave irradiation.Thus, mixtures of a chloride 2 or 10 and an aromatic amine, initially impregnated onto silica gel support by solvent removal of the preliminary prepared dichloromethane solutions, were irradiated in a domestic household microwave oven in open vessels with a power of 800 W, to give the corresponding products 3-9 and 11-17, respectively, as shown on Scheme 1.
ARKAT USA, Inc.The transformation proceeded very clean and fast.No side-product formation was detected.Complete conversion was observed within 3 min in all cases, which leads to a serious energy saving (Table 1).The products were isolated in excellent yields after a very simple work-up; the ammonium salt being filtered off together with the solid support.Analytical and fluorescent grade samples were obtained by purification on a high performance flash chromatography system.a After high performance flash chromatography purification.
The efficiency of the synthetic protocol does not depend on the bulk of the amine used and on the type of the substituents inside the series studied.As can be seen on Table 1, even the relatively hindered 1-naphthyl and 2-methoxyphenyl amines lead to quantitative isolated yields of the products 8 and 14, respectively (entries 6 and 11).
Silica gel was found be an effective solid support, while alumina oxides led to very slow conversion and side-products formation.The amount of the silica gel was optimized and was found that 2 g of per mmol of triazine is the best proportion.
The procedure presents an atom economy protocol as hydrogen chloride is the only byproduct of the reaction.This by-product was quantitatively quenched as ammonium salts during the reaction by the amine, used both as a nucleophile and as a base, thus preventing its release into the environment.
In order to study the role of the microwaves and of silica gel the formation of the melamine 4 was carried out in different reaction conditions, as shown on Table 2.The conversions were followed by 1 H NMR spectra of the crude reaction mixtures by comparing the integrals of the signals for Ar-CH and CH 3 protons of the product with those for morpholino groups, which appear as a common signal for 2 and 4. Solutions of 2 and p-toluidine in decaline and mixtures of the same reagents initially impregnated on silica gel support were both irradiated in a microwave oven with a power of 800 W and heated conventionally at 160 o C. The latter is chosen on the basis of the temperatures measured at the end of the microwave reactions in decalin solution and on silica gel, 154 o C and 162 o C, respectively.As can be seen on Table 2, considerable rate enhancement was observed in the presence of silica gel both under conventional heating and under microwave irradiation (entries 6,7 vs entries 1-3 and entry 8 vs entries 4,5), which is an indication that silica gel significantly promoted the reaction studied.On the other hand, the acceleration detected under microwave irradiation in comparison with the conventional heating in both cases (entries 4,5 vs entries 1-3 and entry 8 vs entries 6,7) demonstrates that microwaves assist the transformation as well.
The absorption spectra of the melamines were studied.All compounds absorb in ethanol at room temperature in the region 48 000 -30 000 cm -1 .It was observed that both electron donating substituents in p-position and prolongation of the conjugated system lead to a bathochromic shift with about 700 cm -1 of the longest wavelength absorption maximum (Figures 1 and Figure 2).

Experimental Section
General Procedures.All reagents were purchased from Aldrich, Merck and Fluka and were used without any further purification.Dichloromethane was dried over calcium hydride.The microwave irradiated reactions (MWI) were performed in domestic household oven Panasonic NN-S255W.Merck silica gel 60 (0.040-0.063 mm) was employed as a solid support.Fluka silica gel/TLC-cards 60778 with fluorescent indicator 254 nm were used for TLC chromatography and R f -values determination.The purifications were carried out on a Biotage Horizon TM HPFC system on silica gel.The melting points were determined in capillary tubes on MEL-TEMP 1102D-230 VAC apparatus without corrections.The IR spectra were taken on a Bruker IFS 113v as KBr discs and were quoted in cm -1 .The electronic spectra were scanned on a Lambda 25 (Perkin Elmer) UV-VIS spectrophotometer in ethanol; the energies of the absorption maxima (the longest wavelength absorption Franck-Condon transitions, ν abs ) were quoted in cm -1 .The NMR spectra were recorded on a Bruker AVANCE DRX 250 spectrometer in deuterochloroform; the chemical shifts were quoted in ppm in δ-values against tetramethylsilane (TMS) as an internal standard and the coupling constants were calculated in Hz.The low resolution mass spectra were taken on a HP 5973 Mass Selective Detector.The microanalyses were carried out by the microanalyses service of the Institute of Organic Chemistry, Bulgarian Academy of Sciences.

Table 1 .
Synthesis of compounds 3

Table 2 .
Synthesis of melamine 4 from 2 in different reaction conditions a Followed by1H NMR spectra of the crude reaction mixtures.b Concentration: 1 mmol 2 and 2 mmol amine in 5 ml decaline.c A temperature of 154 °C was measured at the end of the reaction.d Proportions: 2 g silica gel per 1 mmol 2 and 2 mmol amine.e A temperature of 162 °C was measured at the end of the reaction.