Behavior of 5-amino-3-methylisoxazole in multicomponent heterocyclizations with carbonyl compounds under thermal heating and non-classical conditions

Three-component heterocyclizations of 5-amino-3-methylisoxazole, cyclohexanedione derivatives, and aromatic aldehydes, including salicylic aldehydes, are studied under conventional thermal heating, microwave irradiation and ultrasonication. A dependence of the direction of the reaction on the structure of the aldehyde and the reaction conditions was found, which allowed selective synthesis of 6,7,8,9-tetrahydroisoxazolo[5,4-b ]quinolin-5(4 H )-ones and 2,3,4,9-tetrahydro-1 H -xanthen-1-ones. Key stages of the reaction mechanisms are discussed.


Introduction
One of the main challenges of topical chemistry is the efficient design and synthesis of biologically active molecules.The discovery of high-throughput screening has tremendously increased the demand for new testing compounds and, therefore, multicomponent reactions (MCRs) became increasingly useful tools for the synthesis of biologically active compounds.These reactions enable multi-step syntheses to be conducted in a one-pot fashion to obtain a variety of invaluable products.Moreover, MCRs can dramatically reduce the generation of chemical waste and reduce the cost of the starting materials.In the past several years various multicomponent reactions that can provide easy and rapid accesses to useful functionalized multiple ring structures have been developed.
Isoxazole is an important heterocyclic unit, which has been widely used as a key buildingblock.5][6] Among the isoxazole derivatives, isoxazolopyridines have evoked interest and concern because they showed muscle relaxant, anticonvulsant and CNS depressant activities. 7To the best of our knowledge, multicomponent reactions involving isoxazole core and carbonyl compounds have been insufficiently studied and there have been only a few publications on the subject.For instance, Shi et al. 8 studied the reaction of the aldehydes, mercaptoacetic acid and 5-aminoisoxazole in order to develop diversity-oriented synthesis of novel 1,4-thiazepan-3-ones derivatives embedded with the isoxazole motif.In another publication 9 some new 4-aza-2,3-didehydropodophyllotoxin congeners were synthesized by applying a multicomponent route involving the condensation of substituted aminoisoxazole, tetronic acid and aromatic aldehydes in refluxing ethanol.
Tu and co-authors 10 studied similar microwave-assisted three-component reaction of 5-amino-3-methylisoxazole and aldehydes with several active methylene compounds, such as tetronic acid, Meldrum's acid, 1,3-indanedione and 1,3-cyclohexanediones.There was shown a superior advantage of water as reaction medium and microwave irradiation to promote these treatments.It is worthy to note that, for some reasons which remained obscure, the reaction involving dimedone gave isoxazolo [5,4-b]pyridine while in the case of 1,3-cyclohexanedione the final compound was its dihydro derivative (Scheme 1).

Results and Discussion
The MCR between 5-amino-3-methylisoxazole (1), 4-bromobenzaldehyde (2c), and dimedone (3b) was chosen in order to search for optimal conditions (solvent, activation method, reaction temperature and time).Among the solvents tested (water, different alcohols, DMF, HOAc) water, ethanol and DMF were selected for the model reaction due to better preliminary results.
Ultrasonic-promoted (US) procedures gave the worst results with respect to yields and purity of 4-(4-bromophenyl)-3,7,7-trimethyl-6,7,8,9-tetrahydroisoxazolo [5,4-b]quinolin-5(4H)-one (4l) which was isolated as sole reaction product in the MCR studied (Table 1).The situation was better in the case of conventional heating (Δ) of the starting materials in these solvents -yields of the target heterocycle 4l lay in the range from 50% for EtOH to 75% for DMF while their purity was about 95% (NMR control).However, irrespective of the solvent type, the best yields of the compound 4l (~90%) with high purity were observed when the MCR was carried out under microwave irradiation (MW) at 120 °C.At lower temperatures the yields of compound 4l decreased sufficiently while carrying out the reaction at temperatures higher than 140 °C gave the final heterocycles in unsatisfactory purity or even led to decomposition.Thus, the above-mentioned results for the model three-component reaction allowed us to choose refluxing the starting materials in DMF or the microwave-assisted reaction in ethanol as procedures for the further study.
By using pure ethanol or its mixture with a catalytic amount of Et3N the formation of quinolinones 10 was avoided and only compounds 11a-o and 12a-o were isolated in individual state by crystallization from ethyl acetate.In the case of basic catalysis the mixtures were enriched with compound 11 (75%) while the ratio of 11 and 12 under neutral conditions was 1:1.It can be explained by influence of acidity of the reaction medium on the formation of azomethine since basic additives did not promote the reaction leading to such imines in contrast to neutral or acidic conditions.
It is noteworthy that the MCR of the starting compounds in boiling in DMF in the presence of catalytic amounts of Et3N yielded xanthen-1-ones 13a-c formed without participation of the aminoisoxazole building-block.
Addition to the reaction mixture of a second equivalent of aldehyde allowed directing the MCR in boiling DMF or EtOH towards the exclusive formation of azomethines 12a-o while the selective procedure for the synthesis of compounds 11a-o was not elaborated.
Isoxazolo [5,4-b]quinolinones 10a-o were selectively obtained when 5-amino-3-methylisoxazole 1, diketones 3a-c, and salicylic aldehydes 9a-e reacted in boiling DMF in the presence of catalytic amounts of HCl or Yb(OTf)3 (5 mol %).The yield of this reaction was moderate [45-50% for Yb(OTf)3], however, this result gives a strong background to be elaborated in a future highly effective and selective procedure for the synthesis of compounds like 10 with application of water-stable Lewis acids.
Most likely the three-component reaction of 5-amino-3-methylisoxazole, aldehydes, and derivatives of 1,3-cyclohexanedione pass via formation of Michael adduct I (Scheme 5) and its further cyclization due to the nucleophilic attack at the carbonyl by NH2-group giving up isoxazoloquinolinones 4, 6, 8 or 10.Scheme 4. Oxidation and N-alkylation of heterocycles 4.
However, in the case of salicylic aldehyde (intermediate I') there is an alternative OHnucleophilic reaction center which is able to take part in the heterocyclization with formation of the pyran ring (compounds 11 and 12) instead of the pyridine core.According to experimental data obtained when the salicylic aldehyde is used acidic catalysis with Brønsted or Lewis acids promotes the Hantzsch type of MCR, while a presence in the reaction mixture of Et3N redirects the reaction towards the formation of xanthenones.
Identification of all the compounds synthesized was made with help of elemental analysis, MS spectrometry, 1D and 2D NMR spectroscopy.
Thus,   NOESY spectra of compounds 4, 6, 8 and 10 contain cross-peaks of CH-group and orthoprotons of R-substituent with CH3-group in isoxazole fragment but not with pyridine NH (Fig. 1) allowing excluding the formation of position isomeric structures 16.This fact was additionally proven with COSY and HMBC experiments.The 1 H NMR spectra of the compounds 11a-o and 12a-o contain no signal of NH-and CHgroup from the isoxazole moiety but exhibit broad singlets of NH2 group at 6.35-6.40ppm (for heterocycles 11a-o) or sharp singlet of azomethine CH (8.95-9.05ppm) and signals of protons of second aryl ring (for heterocycles 12a-o).Additionally, the structure of heterocycles 12 was proven by analysis of correlations in HSQC, HMBC and NOESY spectra.
In summary, three-component heterocyclizations between 5-amino-3-methylisoxazole, derivatives of cyclohexanedione, and aromatic aldehydes were studied under conventional thermal heating, microwave irradiation, and ultrasonication.These reactions led to the formation of 4-aryl-6,7,8,9-tetrahydroisoxazolo [5,4-b]quinolin-5(4H)-ones and application of microwave activation in the most cases gave the best results from the viewpoint of yields and purity of the final compounds.Salicylic aldehyde as a substrate complicated the reaction which due to competition of NH2 and OH reaction centers often gave mixtures of 4-(2-hydroxyaryl)-6,7,8,9tetrahydroisoxazolo [5,4-b]quinolin-5(4H)-ones and 2,3,4,9-tetrahydro-1H-xanthen-1-ones.However, variation of the catalyst and the reaction conditions allowed tuning the selectivity of the heterocyclization.Thus, in the presence of Brønsted or Lewis acids heating of the starting materials in DMF or H2O led to the formation of isoxazoloquinolinones while ultrasonication in EtOH-Et3N gave only tetrahydroxanthenones.

Experimental Section
General.The melting points of all compounds synthesized were determined with a Gallenkamp melting point apparatus (for the mixture of diastereomers melting points were not measured).The NMR spectra were recorded at 400 MHz (100 MHz for 13 C) and at 200 MHz (50 MHz for 13 C) with a Varian Unity Plus-400 and Varian Mercury VX-200 spectrometers, respectively.The MS spectra were measured on a GC-MS Varian 1200L (ionizing voltage 70 eV, direct input of the sample) instrument.Elemental analysis was realized on EuroVector EA-3000.Analytical samples of the compounds were obtained by their recrystallization from ethanol and further drying in vacuum at room temperature.Sonication was carried out with the help of standard ultrasonic bath producing irradiation at 44.2 kHz.Microwave experiments were performed using the Emrys Creator EXP from Biotage AB (Uppsala, Sweden) possessing a single-mode microwave cavity producing controlled irradiation at 2.45 GHz.Solvents, all reagents were commercially available and used without additional purification.
General procedure for synthesis of 4a-z, 6a,b and 8a-c.Ultrasonic-assisted synthesis.A mixture of 5-amino-3-methylisoxazole 1 (1 mmol), aldehydes 2a-i (1 mmol), and cyclic β-diketones 3a-c (1 mmol) in ethanol (10 mL) was ultrasonicated at room temperature for 90 min in a round-bottom flask equipped with a condenser.The reaction mixture was allowed to stand up to 12 h at room temperature and then was filtered out to give the solid compounds, which were then washed with acetone and air dried.Reaction products were obtained in high purity and did not require further purification by recrystallization.Thermal heating.A mixture of 5-amino-3-methylisoxazole 1 (1 mmol), aldehydes 2a-i (1 mmol), and cyclic β-diketones 3a-c (1 mmol) in DMF (0.1 mL) was heated to reflux for 10 min.
Then after cooling acetone (10 mL) was added and the precipitate formed was filtered out to give the solid compounds, which were washed with acetone and air dried.Microwave-assisted synthesis.A mixture of 5-amino-3-methylisoxazole 1 (1 mmol), aldehydes 2a-i (1 mmol), and cyclic β-diketones 3a-c (1 mmol) in water (0.1 mL) was irradiated in MW reactor at 120 °C for 5 min.Then after cooling acetone (10 mL) was added and the precipitate formed was filtered out to give the solid compounds, which were washed with acetone and air dried.General procedure for synthesis of 10a-o.A mixture of 5-amino-3-methylisoxazole 1 (1 mmol), aldehydes 9a-e (1 mmol), and cyclic β-di-ketones 3a-c (1 mmol) in DMF (2 mL) in the presence of catalytic amounts of HCl or Yb(OTf)3 (5 mol %) was heated to reflux for 5 min in a roundbottom flask equipped with a condenser.Then after cooling acetone (10 mL) was added and the precipitate formed was filtered out to give the solid compounds, which were washed with acetone and air-dried.

Figure 1 .
Figure 1.Some data of NOESY experiments (a) and alternative structure (b) for compounds 4, 6 and 10.

Table 2 .
Three-component synthesis of compounds 4a

Table 2 .
Continued a ratio (%) of diastereomers according to 1 H NMR data.

Table 3 .
Three-component synthesis of compounds