Alkylation of 2,4-(1H,3H)-Quinazolinediones with Dialkyl Carbonates Under Microwave Irradiations

Alkylation is a very important chemical reaction which modifies the biological properties of drugs. Quinazolinedione derivatives are of considerable interest due to their wide array of pharmacological properties. We now report application of a practical alkylation procedure to several quinazolinediones, including pelanserine (5f), which shows antihypertensive properties, 1‑methyl-3-(2'-phenylethyl)-1H,3H-quinazoline-2,4-dione (1ab) and 1-methyl-3-[2'-(4'-methoxyphenyl)ethyl]-lH,3H-quinazoline-2,4-dione (1ae), which had been isolated from natural sources. The alkylation was optimized using dimethyl and diethyl carbonates under microwave irradiations.

Recently, we synthesized two alkaloids containing the quinazoline-2,4-dione ring skeleton -1-methyl-3-(2'-phenylethyl)-1H,3H-quinazoline-2,4-dione (1ab) and 1-methyl-3-[2'-(4'-methoxyphenyl)ethyl]-lH,3H-quinazoline-2,4-dione (1ae) -which have been isolated from the seed husks of Zanthoxylum arborescens [28]. Alkylation reactions were performed with methyl iodide and TMG as a base, but the reagents are expensive abd toxic and take about one hour at 55 0 C to complete the reaction [29]. Herein, we propose a novel methodology for the alkylation using inexpensive dimethyl and diethyl carbonates which are very stable liquids, non-reactive under normal conditions. The reactions were assisted and optimized by microwaves, taking only a few minutes to complete. This efficient process was applied to a quinazolinedione library to improve the methodology without toxic reagents.

Results and Discussion
Alkylation of NH-containing heteroaromatic compounds is an important transformation that regularly employs toxic and hazardous reagents such as methyl iodide [29] or dimethyl sulfate [30]. Dialkyl carbonates are an attractive alternative as alkylating reagents for NH-containing heteroaromatic compounds. Quinazoline-2,4-diones 5(a,b,c,d,e,f) were thus prepared using our methodology [26]. Initially, we prepared the ortho-aminobenzamides from the reactions of isatoic anhydride with amines and the cyclization was carried out with bis(trichloride methyl)carbonate (BTC, triphosgene). Finally, the alkylation with dimethyl carbonate was optimized under microwave irradiation and the conditions were fixed at 200 W, 130 °C, for 15 minutes, using K 2 CO 3 as base 5f 5b (R 1 =H), 5e (R 1 =OCH 3 ) (Scheme 1). The reaction was filtered, to get a >94% yield. The alkylation with diethyl carbonate was similar, in this case it was necessary to increase the temperature to 160 °C to obtain the ethylquinazoline-2,4-diones in a >92% yield. Ethylation products had to be purified by column chromatography on silica gel to remove the excess of diethyl carbonate. By applying microwave irradiation further rate enhancements were accomplished.

Scheme 1.
Steps to obtain to the N-methyl quinazoline-2,4-diones. The new methodology has the advantages of rapid reaction times, ease of operation and purification and the use of readily available reagents, and the avoidance of toxic alkylating reagents. In this work methyl and ethyl quinazoline-2,4-dione libraries were prepared, which are detailed in Table 1. The yields obtained with the optimized method were excellent, with conversions of 92-98%. Therefore, this is a very efficient method, with easy purification of products, since no by-products were observed.

Conclusions
We have developed a simple method to methyl or ethyl alkylation of amide-NH functions with dialkyl carbonates, which were assisted by microwave irradiation. We used several quinazoline-2,4diones which were previously synthesized by our group for biological evaluation as potential antihypertensive agents. We have proven that this method is very fast, clean, with almost complete conversion, using stable reagents avoiding possible contamination. We are currently exploring this reaction without solvent, as a green chemistry process. The amounts of K 2 CO 3 are important which were established at three equivalents, thus working in a more efficient way. After several experiments, optimum conditions were determined. The basic backbone provides a source for introduction of different heterocyclic extension on the amide -NH, in order to diversify the quinazoline-2,4-dione structural system.

General
Melting points were measured on an Electrothermal 88629 apparatus and are uncorrected. Infrared (IR) spectra were recorded on a Perkin Elmer FT-IR 1600 spectrometer. 1 H-NMR and 13 C-NMR spectra were recorded at 200 MHz and 50.289 MHz, respectively, on a Varian Mercury 200 spectrometer in CDCl 3 with TMS as internal standard. Mass spectra were obtained on an Agilent 1100 series LC/MSD Trap, SL Spectrometer by electrospray insertion. Microwave equipment was a selftuning single mode CEM Discover TM Focused Synthesizer.