Synthesis of substituted 1,3-oxazino[5,4,3-ij ]quinolin-1,3-diones by the oxidation of various pyrrolo[3,2,1-ij ]quinoline-1,2-diones with m -chloroperbenzoic acid

When various pyrrolo[3,2,1-ij ]quinoline-1,2-diones were oxidized with m -chloroperbenzoic acid, 1,3-oxazino[5,4,3 -ij ]quinolin-1,3-diones were obtained in good yields (64 – 86%) and characterized by spectral methods. Recyclization/rearrangement of the pyrroldione fragment of pyrrolo[3,2,1-ij ]quinoline-1,2-diones, regardless of the presence and electronic nature of the substituent in the aromatic part, the presence of a bulky phenyl group or a multiple bond in the heterocyclic fragment, proceeds selectively with the formation of a 1,3-oxazine cycle, rather than an isomeric 1,4-oxazine ring. This outcome corresponds to the data acquired from quantum mechanical calculations


R N
Earlier, based on oxidative transformations of the tricyclic analogue of isatin -pyrrolo[3,2,1-ij]quinoline-1,2-dione (5) under the action of peracids, we synthesized 1,3-oxazino [5,4,3-ij]quinoline-1,3-dione (6) and its isomer -1,4-oxazino [2,3,4-ij]quinoline-2,3-dione (7) (Scheme 2). 38Previously, we also showed that various substituted pyrrolo[3,2,1-ij]quinoline-1,2-diones 8 and 9, as well as isatin, undergo opening of the pyrroledione fragment and subsequent decarboxylation under the action of hydrogen peroxide in an alkaline medium, with the subsequent formation hydroquinoline-8-carboxylic acids 10 and 11, respectively (Scheme 2). 39In addition, the presence of a gem-dimethyl fragment in the ortho position from the nodal nitrogen did not sterically hinder this decyclization.In order to obtain new oxazinohydroquinolines, and to establish their structure, in this work we carried out the oxidation of 4,4,6-trimethyl-4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones 9 and their hydrogenated analogs, 4,4,6-trimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-diones 8, with m-chloroperbenzoic acid.-e) were prepared according to the Stolle method, 40 which we had previously modified 41,42 by reacting the hydrochlorides of the corresponding starting substituted hydroquinolines with oxalyl chloride (without using Lewis acids as catalysts, which are required for cyclization in the classical version of the reaction).In a previous paper 38 we developed optimal conditions for the selective oxidation of pyrrolo[3,2,1-ij]quinoline-1,2-dione 5 in THF, leading to the formation of 1,3-oxazinoquinolinedione 6.This process involved a solution of mchloroperbenzoic acid in THF being added in small portions at a temperature of -2-3 °C, after which the reaction mixture was kept at room temperature for 4-5 hours.In this paper, we have studied the oxidation of pyrrolo[3,2,1-ij]quinoline-1,2-diones 9a-e and 8a-f without substituents and having acceptor fluorine atoms or various electron-donating substituents on the benzene ring, including compound 8f containing two substituents (methyl and phenyl group) in the para position relative to the nitrogen atom in the hydropyridine fragment.The oxidation of all pyrroloquinolinediones 8 by this method proceeded smoothly (regardless of the presence and electronic nature of the substituents on the aromatic part or the presence of a bulky phenyl group in the heterocyclic fragment).After 3 hours, the reaction mixture began to change color from orange to light yellow, which allowed visual analysis of the reaction progress.Within 4-5 hours the reaction was deemed complete, and the reaction products precipitated after removal of excess solvent on a rotary evaporator.After purification from the mixture of m-chlorobenzoic acid by recrystallization from CCl4, the products yields were 64-86%.Using a combination of 1 H NMR and 13 C NMR spectroscopy and mass spectrometry data, the reaction products could be assigned the structures, 9-R-7-R'-5,5,7-trimethyl-6,7-dihydro-1H,5H- [1,3]oxazino [5,4,3-

Results and Discussion
The structure of the compounds obtained, 10a-f, was unambiguously confirmed by 1 H and 13 C NMR spectroscopy and mass spectrometry.In the 1 H NMR spectra of all 1,3-oxazinoquinolines 10, the proton signals of the gem-dimethyl groups and other substituents at positions 7 and 9 of the hydroquinoline fragments appear in the corresponding regions. 39,41,42.It should be noted that in the aromatic areas of the spectra, the signals of some protons of the hydroquinoline cycles were shifted quite downfield -up to 8.0 ppm, which we observed earlier in previous research. 38This shift can be associated with the presence of an intramolecular hydrogen bond between a proton and an adjacent carbonyl group in the 1,3-oxazine ring. 33The presence of a characteristic signal of an aromatic carbon atom at 158-160 ppm in the 13 C NMR spectra of the obtained compounds 10 and the absence of peaks in the region of 150-152 ppm indicated that the aromatic ring is associated with a carbonyl carbon, 33,38 but not with an oxygen atom. 36,38n the mass spectra (EI) of oxazinoquinoline-1,3-diones 10a-f, peaks of molecular radical ions of low intensity (Irel = 10 -21%,) were observed.The maximum intensity and (Irel = 100%) were possessed by the ions formed during the elimination of a CO2 molecule and a methyl radical from the molecular radical ions.Elimination of the latter is characteristic of the decomposition of molecular ions of hydroquinoline derivatives with a gem-dimethyl group in the second position. 43The decay of a molecular radical ion with the release of a CO2 molecule additionally confirmed the structure of 1,3-oxazinoquinolines 10, ascribed to the obtained compounds, rather than 1,4-oxazinoquinolines 11, the decomposition of which should occur with the successive release of two CO molecules. 38n terms of the reaction mechanism, presumably, at the first stage of the process, the peracid is added to the carbon atom of the carbonyl group with the formation of intermediates 8'a-f, the subsequent recyclization/rearrangement of which, due to the opening of the pyrrole ring (by bond a), leads to the formation of compounds 10 (Scheme 3).It should be noted that in the case of pyrroloquinolinediones 8, we failed to direct the reaction along the route involving the opening of bond b, according to the method described 36 for the preparation of 1,4-oxazines.Oxidation of pyrroloquinolinediones 8 by this method, when the entire amount of m-chloroperbenzoic acid was added at once at room temperature (even in the presence of electron donor groups in the hydroquinoline fragment of these compounds), did not lead to the expected 7-R-9-R'-5,5,7trimethyl-6,7-dihydro-5H- [1,4]oxazino [2,3,4-ij]quinoline-2,3-diones 11a-f.As a result, using this technique, we obtained products that were completely identical in terms of melting point and TLC data to 1,3oxazinoquinolines 10a-f, and their yields did not significantly differ.
In terms of understanding the outcome of the reactions performed, it was decided to investigate the substrates by computational methods.For all the molecules, a complete geometry optimization was also performed using the B3LYP exchange-correlation density functional in the cc-pVDZ basis set.Calculation and analysis of normal vibrations of molecules showed that the optimized structures correspond to the energy minimum on the potential energy surface.The calculation of charges on atoms was carried out using the method based on the reproduction of the molecular electrostatic potential CHELPG. 46This method of calculating charges on atoms shows more accurate results, which are less dependent on the choice of the basis set.All quantum chemical calculations were performed using the Gaussian 09 program. 47n terms of outcomes, the quantum-chemical calculations of atomic charges in compounds 8 and 9 (Figure 1) showed that quite large positive charges are localized on the C 1 and C 2 atoms, while the C 9a atom bears a weak negative charge.This explains why the recyclization/rearrangement of the pyrroledione fragment into the oxazine fragment preferentially proceeds with the breaking of the bond between the C 1 and C 2 atoms.

AUTHOR(S)
An alternative variant of recyclization/rearrangement, due to the breaking of the bond between the C 1 and C 9a atoms, does not occur, even in the presence of substituents in the 6th and 8th positions of pyrroloquinolines 8 and 9, since the influence of the substituent is reflected only on the charges of the C 6 and C 8 atoms and practically does not affect the charges of the C 1 , C 2 atoms and C 9a (Table 1).
Commercially available reagents from Lancaster were used in the syntheses.The starting compounds 8a-f and 9а-e were synthesized according to literature procedures. 42The solvents were purified according to standard methods.

Table 1 .
Calculated atomic charges according to CHELPG on the atoms of compounds 8 and 9 * The numbering of the atoms is given according to the Scheme 3.