One-pot synthesis of 5 H -chromeno[3,4-b ]pyrazin-5-one derivatives from 4-amino-3-nitrocoumarin and α -dicarbonyl compounds

2,3-Disubstituted [3,4]-fused pyrazinocoumarins have been synthesized in very good yields by the one-pot reaction of 4-amino-3-nitrocoumarin with α -dicarbonyl compounds in the presence of PPh 3 in n -pentanol under microwave irradiation. The reactions of 3,4-diaminocoumarin with α -dicarbonyl compounds in o -xylene under microwaves led also to the title compounds in excellent total yields

Generally, the synthesis of pyrazines has been achieved through self-condensation of α-aminoketones 17 or through intramolecular hydroamination/isomerization/ aromatization sequence of N-Boc-protected 2-(propargylamin)acetaldehyde oximes in the presence of catalytic amount of p-toluenesulfonic acid under microwave irradiation 18 or by the reactions of propargylamine with aldehydes in the presence of (Ph3P)AuNTf2 as a catalyst. 19The synthesis of fused benzopyrazine has been performed by the condensation of glyoxal with o-phenylenediamine under reflux, 20 while substituted benzopyrazines have been received through condensation of benzil derivatives with o-phenylenediamines in the presence of 2-iodoxybenzoic acid (IBX). 21riphenylphosphine (PPh3) is a useful reagent for the reduction of nitrogen containing compounds like azides 22 (Staudinger reaction), nitroso compounds 23 and N-oxides. 246][27] Recently, we performed the one-pot synthesis of fused oxazolocoumarins and imidazolocoumarins from o-hydroxynitrocoumarin or o-aminonitrocoumarin, respectively, using the PPh3 as reducing agent in the presence of carboxylic acids. 28,29We envisioned that this reaction could also work for the one-pot synthesis of pyrazolocoumarins from 4-amino-3-nitrocoumarin and α-dicarbonyl compounds.Herein, we present our investigations towards this goal.

Results and Discussion
The studied reactions and the products obtained are depicted in Scheme 1.The starting 4-amino-3nitrocoumarin (1) was prepared from 4-chloro-3-nitrocoumarin, 30 according to our recent modification, 29 by the treatment with 7M methanolic solution of NH3.We select glyoxal (2a) as a model substrate to test the suitable conditions for the application of the one-pot tandem reaction of 1 with α-dicarbonyl compounds.The reaction of 1 with 2a in the presence of PPh3 (3), using o-xylene as solvent under microwave irradiation at 130 ᵒC for 15 h resulted to 5H-chromeno [3,4-b]pyrazin-5-one (4a) in low yield (Table 1, entry 1).Changing the solvent to n-butanol, a protic solvent, at 140 ᵒC for 10 h the yield of the reaction increased to 34%, with 60% of the starting compound to remain unchanged (Table 1, entry 2).The use of n-pentanol (Method A) at higher temperature (170ᵒC) under microwave irradiation for 8 h led to 4a in 66% yield (Table 1, entry 3).In consequence, we applied this method for the one-pot synthesis of [3,4]-fused pyrazinocoumarins 4 and 5 from 4-amino-3-nitrocoumarin (1) and α-dicarbonyl compounds 2a-h.
The reactions of 1 with methylglyoxal (2b) or phenylglyoxal (2c) at 170 ᵒC for 6 or 7 h led to the fused pyrazinocoumarins 4b and 5b or 4c and 5c, respectively (Table 3, entries 4 or 5).The higher yields of the products 4b and 4c, in comparison to their isomers 5b and 5c, reveals the increased reactivity of formyl group to acetyl or benzoyl group. 31As the 4-amino group of coumarin of the intermediate 3,4-diaminocoumarin has less nucleophilic character due to the conjugation with the carbonyl of coumarin, 32,33 the 3-amino group reacted first with the formyl group followed by the condensation of 4-amino group with the acetyl or benzoyl group.HMBC experiments for the above products confirmed the proposed structures of those isomers, as pyrazine protons H-3 of 4b and 4c show interaction with the C-3 (C-4a) of the coumarin ring (Supplementary Information, S6, S13).
As we observed above, Method B is better than Method A. Generally (except for the case of 4d), the synthesis of fused pyrazinocoumarin derivatives by the condensation of 3,4-diaminocoumarin (6) (prepared before from 1) with α-dicarbonyl compounds 2a-h (Method B) was achieved in very good to excellent total yields in less reaction time.The one-pot synthesis of those derivatives (Method A) led to the products in moderate to good yields by spending enough time for the completion of the reactions.In order to explain the one-pot synthesis of the products, we could assume that PPh3 (3), as a modification of Cadogan reaction, was added to the nitro-group of 4-amino-3-nitrocoumarin (1) and by abstraction of Ph3PO gave as intermediate the 4-amino-3-nitrosocoumarin (A) (Scheme 2), in analogy to the reductive cyclization of 2-nitrobiphenyls to carbazoles in the presence of 3. 35 New addition of 3 to the nitroso-group of A resulted possibly, to the nitrene B, after removing of Ph3PO.Hydrogenation of B by the acidic proton of the present alcohol led to the 3,4diaminocoumarin (6), as it has been checked by the TLC of a blanc experiment, without the presence of glyoxal (2a).Pyrazinocoumarin 4a was synthesized by the condensation of 6 with the 2a.Scheme 2. Proposed mechanism for the one-pot reaction of 1 with 2a in the presence of PPh3.

Conclusions
In conclusion, 2-or/and 3-substituted [3,4]-fused pyrazinocoumarins were synthesized in very good to excellent yields by the reactions of 3,4-diaminocoumarin with α-dicarbonyl compounds under microwave irradiation for a short time.The one-pot reaction of 4-amino-3-nitrocoumarin with α-dicarbonyl compounds in the presence of PPh3 under microwaves in n-pentanol led also to the title compounds in moderate to very good yields, but under longer reaction time and higher temperature.Most of the synthesized derivatives are new compounds.

Experimental Section
General.All the chemicals were procured from either Sigma-Aldrich Co. or Merck & Co., Inc.Melting points were determined on a Kofler hot-stage apparatus and are uncorrected.IR spectra were obtained with a Perkin-Elmer 1310 spectrophotometer as KBr pellets.NMR spectra were recorded on a Agilent 500/54 (DD2) (500 MHz and 125 MHz for 1 H and 13 C respectively) or on a Agilent AM600 (600 MHz and 150 MHz for 1 H and 13 C respectively) using CDCl3 as solvent and TMS as an internal standard.J values are reported in Hz.Mass spectra were determined on a LCMS-2010 EV Instrument (Shimadzu) under Electrospray Ionization (ESI) conditions.HRMS (ESI-MS) were received on Agilent Q-TOF Mass Spectrometer, G6540B model with Dual AJS ESI-MS.Silica gel N o 60, Merck A.G. was used for column chromatography.The MW experiment was performed in a scientific focused microwave reactor (Biotage Initiator 2.0).4-Amino-3-nitro-2H-chromen-2one (1) and 3,4-diamino-2H-chromen-2-one (6) were prepared according to our recent publication. 29