Novel synthesis of 1-alkyl-4-tosyl-3-carboxymethyl-1 , 2 , 3 , 4-tetrahydroquinoxalin-2-ones

1-Alkyl-4-tosyl-3-carboxymethyl-1,2,3,4-tetrahydroquinoxalin-2-ones were synthesized by means of a key step that consisted in a condensation reaction between o-phenylenediamine and maleic anhydride, followed by tosylation and final alkylation. The X-ray diffraction of 3carboxymethyl-4-tosyl-1,2,3,4-tetrahydroquinoxalin-2-one benzyl ester (1e) and 1-benzyl-3carboxymethyl-4-tosyl-1,2,3,4-tetrahydroquinoxalin-2-one benzyl ester (1f) is reported.


Introduction
Quinoxalin-2-ones display interesting biological properties, including the inhibition of the aldose reductase enzyme, 1 partial agonists for complex receptors γ-aminobutyric acid (GABA)/benzodiazepine 2 and as multiple-drug-resistance antagonists, 3 amongst others.Additionally, the quinoxalin-2-one, Figure 1, has been used as an intermediate in the preparation of diverse derivatives with antimicrobial, 4 antifungi, 5 antiviral 6 and anticancer 7 activity.Herein, we report a novel synthetic route to a series of novel compounds 1-alkyl-4-tosyl-1,2,3,4-tetrahydroquinoxalin-2-one with CH 2 CO 2 R group in position 3 (1a-i), Figure 2. The key step of this route involves the condensation of o-phenylenediamine (2) with maleic anhydride (3) that leads directly to the basic backbone, Scheme 1.The quinoxalin-2-ones 1 have groups CH 2 CO 2 R (R = H, alkyl), in position 3, and were functionalized in N1 and N4 positions.The tosyl group in N4 has been shown to be responsible for the inhibition of the aldose reductase enzyme, in vitro and in vivo, 1 whereas the substituent in N1 modifies the solubility of the molecule.

Results and Discussion
][5][6][9][10][11] The most common synthesis of these molecules is the cyclization of o-phenylenediamine, or substituted derivative, with an α-haloester under basic conditions.However, this route involves at least three steps giving moderate yields, Scheme 2. 2a-b, In another reported methods, the ARKAT USA, Inc.
quinoxalinones has been prepared in solution 2a, 10a and on solid support 9, 10b from α-amino acid esters and 2-fluoronitrobenzenes.Thus, we decide to look for a convenient synthesis of tosylated compounds 1b-i, through the condensation reaction of o-phenylenediamine (2a) with the maleic anhydride (3).When the condensation of o-phenylenediamine with maleic anhydride was carried out at room temperature in THF, the expected compound 1a was not obtained, instead the (Z)-3-(2aminophenylcarbamoyl)propenoic acid (8a) 12 was the main reaction product (98 %).Compound 8a is the product of a partial condensation of the reagents, when we have tried to close the ring, we noted that 8a is unstable and under air exposure or in basic medium is rapidly transformed into the 3-methylquinoxalin-2-one (10).This observation was important because, it implies the formation of two intermediates (1a and 9), Scheme 3. We have observed that after 6 h in refluxing THF and in N 2 atmosphere, the acid 8a was partially transformed into the 1,2,3,4tetrahydroquinoxalin-2-one 1a.(10).
Due to the fact that compound 1a in our previous attempts was obtained in low yield, we used a catalyst in order to promote the cyclization and to prevent oxidation-decarboxylation, and therefore an antioxidant (butylated hydroxytoluene BHT) was incorporated into the reaction.The decomposition of 1a into 10 was avoided and the yield was improved (86 %, after crystallization), while only 4.7 % of acid 8a was formed, Scheme 4. When the 4-nitro-1,2phenylenediamine (2b) react with maleic anhydride, the (Z)-3-(2'-amino-5'nitrophenylcarbamoyl)propenoic acid (8b) was obtained in 100 %.It is important to indicate that the reaction of maleic anhydride with 4-substitued o-phenylenediamines (e.g.4-Cl or 4-OMe) gave a mixture of not identified products.Once the quinoxalin-2-one 1a was obtained, it turns out to be relatively stable and easy to purify.Nevertheless, it is important to indicate that when 1a is either directly exposed to the air or dissolved in a basic medium, it is transformed into the oxidized compound 10.This situation makes difficult the subsequent selective protection of N1 and/or N4, because these reactions are generally carried out in basic medium.
The reported basic conditions for tosylation of 1,2,3,4-tetrahydroquinoxalin-2-ones 1 (suspension of Na 2 CO 3 and tosylchloride in acetone under N 2 atmosphere and 18 h of reaction) were inappropriate for 1a, due to decomposition.For this reason, we developed a novel tosylation procedure that consisted in controlling the pH (5.5) of the reaction medium using a buffer dibasic sodium phosphate solution [0.1 M], Scheme 5.The 3-carboxymethyl-4-tosyl-1,2,3,4-tetrahydroquinoxalin-2-one (1b) precipitated from the reaction mixture and was obtained in 73 % yield after crystallization.The tosyl group in 1b increases its stability allowing the N1 alkylation.The N1 alkylation of tetrahydroquinoxalin-2-ones with benzyl and allyl halides in the presence of 2-t-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) in DMF 13 , as well as the alkylation with ethyl bromoacetate and NaH in dioxane 1 have been reported.In our research, this alkylation was performed under phase transfer catalysis conditions of compound 1b, employing a catalytic amount of tetrabutylammonium hydrogensulphate (TBAHS).The reaction time was variable and depends on the alkyl halide reactivity and amount, Scheme 6.The esters 1c, 1e and 1g were obtained in moderate to good yields and the N1 alkylation products 1d, 1f, 1h and 1i gave in low to good yields (<71 %).The formation of the esters was simply confirmed via the existence of the set of carbons in its 13 C NMR spectrum.The low yield for 1d is probably due to "poisoning" of the phase transfer agent with methyl iodide.The structures of 1e and 1f were confirmed by single-crystal X-ray crystallography.A perspective view of 1e and 1f, together with the atom-numbering scheme, are shown to left of Figures 3 and 4, respectively.All interatomic distances can be considered normal.The sidebranch conformation in C3 in 1e and 1f is comparable and may be explained by intramolecular C-H···N hydrogen bonds between N4 and H20.This interaction approaches the phenyl ring to atom N4.
Conformational analysis of the puckered heteroatom ring of the quinoxalinone system, in 1e shows an intermediate conformation between screw-boat and envelope.The total puckering amplitude is Q T = 0.410 Å, calculated by the Cremer-Pople method. 15Molecules of 1e are held together by N-H···O intermolecular hydrogen bond between H1 and O2 and intermolecular C-H···O between H9 and O10b forming a six member ring, see right image shown in Figure 1.
Compound 1f shows a screw-boat conformation.The total puckering amplitude is Q T = 0.508 Å.The molecules of 1f are held together by C-H···O interactions between H7 and O4, a sulphonamidic oxygen, see right image of Figure 2. The benzyl group in N1 of compound 1f have an perpendicular orientation respect to quinoxalinone system.This is attributed to hindrance interactions.
The conformational differences between 1e and 1f can be attributed to benzyl substituent in N1-of 1f.

Conclusions
We have developed a novel approach for the synthesis of N1 and C3 substituted 4-tosyl-1,2,3,4tetrahydroquinoxalin-2-ones through a cyclization reaction between maleic anhydride and ophenylenediamine, followed by tosylation and a subsequent alkylation reaction under a phase transfer catalysts.The newly developed methodology is general to allylic and benzylic substituents and provides quinoxalinones C3 substituted in moderate to good yields depending on the nature used in the final alkylation step.

Experimental Section
General Procedures.All commercially available chemicals were reagent grade and used without further purification.The chromatographic purification was made on flash column chromatography using silica gel (230-400 mesh, 60 Å).The melting points are uncorrected.IR spectra were obtained from a Perkin-Elmer spectrum GX instrument using KBr plates for solid samples and CHCl 3 solution for liquid samples.The low resolution mass spectra were obtained by direct insertion at 20 eV in a HP 5989 spectrometer.The samples were ionized electronically (EI).HRMS data were obtained in HPLC equipment coupled to MSD TOF Agilent.If not stated otherwise, the NMR spectra were measured in DMSO-d 6 using TMS as internal standard for 1 H and 13 C NMR spectroscopy. 1 H NMR: 400, 300, and 270 MHz spectrometers. 13 means of { 1 H, 1 H}-COSY and { 1 H, 13 C}-HETCOR experiments.For the crystallographic study of 1e and 1f, data were measured on a Nonius Kappa CCD instrument with area detector using graphite-monocromated Mo Kα radiation.Intensities were measured using ϕ + ω scans.Structures were collected at 173 and 293 K, respectively.Crystals of 1e and 1f were obtained from hexane/AcOEt, they are triclinic space group P-1 [a = 8.6123 ( 2 In both structures, all hydrogen atoms were located and their positions were refined and solved by direct methods using SHELX-97, 16 and the refinement (based on F 2 of all data) was performed by full matrix least-squares techniques.All non-hydrogen atoms were refined anisotropically.Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre as numbers: 654371 (1e) and 654372 (1f).Copies of the data can be obtained, free of charge, on applications to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].

Scheme 5 .
Scheme 5. Tosylation reaction of 1a in a buffer solution.