A Simple and Convenient Method for the Synthesis of 1-Methyl-7-arylfuro[3,2-g]pteridine-2,4(1H,3H)-diones and Their Substituted Derivatives

A simple and effective method for the synthesis of unknown 1-methyl-7-arylfuro[3,2-g]pteridine-2,4(1H,3H)-diones by dehydration of the corresponding 1-methyl-6-phenacyl-pteridine-2,4,7(1H,3H,8H)-triones is reported in the article. It was shown that their alkylation by butyl chloroacetate in basic medium proceeded by the N3-atom of the heterocycle. The structure and purity of the synthesized compounds were confirmed by IR, 1H, 13C NMR spectroscopy, gas chromatography-mass spectrometry, mass spectrometry, as well as X-ray diffraction analysis. The proposed mechanism of the dehydration reaction was discussed.


1. Chemistry
Melting points were determined in open capillary tubes in a Mettler Toledo МР 50 apparatus and are uncorrected. The elemental analyses (C, H, N) were performed using the ELEMENTAR vario EL cube analyzer (USA) and are within ±0.3% of the theoretical values. IR spectra (4000-600 cm -1 ) were recorded on a Bruker ALPHA FT-IR spectrometer (Bruker Bioscience, Germany) using a module for measuring attenuated total reflection (ATR). 1 H NMR spectra (400 MHz) were recorded on a Varian-Mercury 400 (Varian Inc., Palo Alto, CA, USA) spectrometers with TMS as internal standard in DMSO-d 6 solution. 13 C NMR spectra of compounds (3b-e, 3g-j, 100 MHz) were recorded in TFA-d 1 solution. LC-MS were re-
It should be noted that dehydration of compounds 1a-k (A in Scheme 2) in the solution of polyphosphoric acid proceeded according to the Paal-Knorr synthesis. 21 The mechanism of this reaction assumes the nucleophilic attack of the amide fragment oxygen atom of the molecule at the carbon atom of the protonated carbonyl group (B). The oxonium cation C became aromatic in the result of deprotonation and dehydration with the formation of the final product E.
To increase the solubility of 1-methyl-7-arylfuro[3,2-g]pteridin-2,4(1H,3H)-diones 2a-k in organic solvents (DMSO, DMF), the next step was to study their alkylation. It was found that alkylation of compounds 2a-k by butyl chloroacetate in DMF in the presence of K 2 CO 3 proceeded by the N 3 -atom of the heterocycle. Corresponding esters 3a-j were formed with satisfactory yields (Scheme 1). In this cases, compounds 3a-j have higher solubility in organic solvents.
The formation of compounds 2a-k was indicated by 1 H NMR spectra. Such singlet signals of proton at the 6 th position were recorded in the region of 8.14-7.49 ppm. However, these protons were in some cases (compounds 2f and 2h) recorded as multiplets together with the signals of protons of the substituent at the 7 th position. Protons at the 3 rd position of compounds 2a-k were found in the range of 12.03-11.44 ppm in the low-field part of the 1 H NMR spectra. Speaking about compounds 3a-j, the characteristic signal of the proton at the 6 th position was recorded at 8.19-7.69 ppm. At once, in the 1 H NMR spectra of com-pounds 3a-j, unlike compounds 2a-k, there were singlet signals of protons of the NCH 2 group at 4.74-4.76 ppm and a series of proton signals of a butoxycarbonyl fragment. Also, in the spectra of compounds 2a-k and 3a-j there were singlet signals of methyl group protons at 3.57-3.72 ppm and a set of signals corresponding to the substituent at the 7 th position. 22 Additionally, the formation of furo[3,2-g]pteridine-2,4(1H,3H)-diones 2a-k was confirmed by the 13 C NMR spectrometry when studying their more soluble esters 3. The characteristic signals in the 13 C NMR spectra of compounds 3a-j were: signals of carbon atom at the 6 th position at 106.4-95.1 ppm, signals of carbon atoms of the COO-group at 168.1-172.7 ppm and signals of NCH 2 CO-fragment at 43.2-43.6 ppm. The positions of other signals in the 13 C NMR spectra correspond to the proposed structures. 23 The analysis of the data of the chromato-mass spectra confirmed structure and purity of the compounds 2a-k and 3a-j. An additional analysis of the mass spectra (EI) of compounds 2a and 3a showed the fragmentation of the furo[3,2-g]pteridine system. Thus, the high stability of the molecular ion of compound 2a ([M] •+ , m/z = 294, I rel = 66.8%), determined its fragmentation along the less aromatic dihydropyrimidine cycle with a step-by-step release of HNCO molecules (F 1 , m/z = 251, I rel = 12.6%), CO (F 2 , m/z = 223, I rel = 100%) and the NCH 3 • ion (F 3 , m/z = 194, I rel = 10.5%). Formed 6-phenylfuro[2,3-b]pyrazine ion (F 3 ) eliminated two НСN molecules with formation of ions with F 4 (m/z = 167, I rel = 5.9%) and F 5 (m/z = 140, I rel = 24.8%), while for F 5 formation of two alternative fragmentation ions [С 6 Н 5 ] •+ (m/z = 77, I rel = 25.3%) and [С 4 Н 3 О] •+ (m/z = 67, I rel = 16.8%) was characteristic. Whereas, the molecular ion of ether 3a was less stable ([M] •+ , m/z = 408, I rel = 46.6%). The main ways of its fragmentation were associated with the initial elimination of С 4 H 9 + (F 1 , m/z = 352, I rel = 10.6%) and СО 2 (F 2 , m/z = 308, I rel = 31.9%). Further degradation of the fragmented ion (F 2 ) proceeded similarly to the path described for compound 2a, which led to the appearance of signals with m/z = 251 (I rel = 9.5%), m/z = 223 (I rel = 23.9%) and m/z = 140 (I rel = 10.2%).
The final structure of compound 2a was confirmed by X-ray diffraction study (Fig. 1). It was found that it crystallized in the non-centrosymmetric space group P21, despite the absence of chiral centers in the molecule (Fig. 1).
All non-hydrogen atoms in the molecule lie in the plane with an accuracy of 0.05 Å, despite the presence of slight steric repulsion between the atoms of the tricyclic fragment and the phenyl substituent (shortened intramolecular contacts H(11)•••C(5) 2.79 Å with the sum of the van der Waals radii 24