Preparation of Quinoline-2,4-dione Functionalized 1,2,3-Triazol-4-ylmethanols, 1,2,3-Triazole-4-carbaldehydes and 1,2,3-Triazole-4-carboxylic Acids

(1-(2,4-Dioxo-1,2,3,4-tetrahydroquinolin-3-yl)-1H-1,2,3-triazol-4-yl)methyl acetates substituted on nitrogen atom of quinolinedione moiety with propargyl group or (1-substituted 1H-1,2,3-triazol-4-yl)methyl group, which are available from the appropriate 3-(4-hydroxymethyl-1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-diones unsubstituted on quinolone nitrogen atom by the previously described procedures, were deacetylated by acidic ethanolysis. Thus obtained primary alcohols, as well as those aforenamed unsubstituted on quinolone nitrogen atom, were oxidized to aldehydes on the one hand with pyridinium chlorochromate (PCC), on the other hand with manganese dioxide, and to carboxylic acids using Jones reagent in acetone. The structures of all prepared compounds were confirmed by 1H, 13C and 15N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments (1H–1H gs-COSY, 1H–13C gs-HSQC, 1H–13C gs-HMBC) with 1H–15N gs-HMBC as a practical tool to determine 15N NMR chemical shifts at the natural abundance level of 15N isotope.


Results and Discussion
Compounds 1, 2 and 3 ( Figure 1) were obtained through the multistep synthetic pathway, which we have developed recently, 30 and were utilized as starting compounds in this study.
Although acetates 1a,b were prepared by acetylation of the corresponding primary alcohols 4a,b, 30 we exploited them as model compounds and dealt with finding a suitable procedure for their deacetylation back to the mentioned alcohols so that we can apply it to prepare alcohols 5a,b and 6a-f from the more laboriously obtainable corresponding acetates 2a,b and 3a-f. At first, we tried processing with a methanolic solution of sodium methoxide, however, in parallel with ester methanolysis, undesirable nucleophilic quinoline-2,4-dione ring opening and successive reactions took place resulting in mixtures, from which only corresponding N-substituted anthranilic acids and eventually their methyl esters were isolated after neutralization with diluted hydrochloric acid. Also alkaline hydrolysis of ester group is accompanied with above mentioned ring opening; the treatment of 1b with a solution of potassium hydroxide in aqueous ethanol afforded corresponding anthranilic acid as main product.
Finally, acidic alcoholysis (37% HCl : EtOH 1:100 v/v) has proved to be suitable. After the successful deacetyl-  ation of compounds 1a,b, this method was applied also to deacetylation the acetates 2a,b and 3a-f. This reaction was carried out by boiling the reaction mixtures and was finished in 2.5-4 hours. The appropriate primary alcohols were obtained with yields 80-90% (see Table 1). The reaction conditions of the conversion of prepared alcohols to the corresponding aldehydes were optimized for the oxidation of alcohols 4a,b to aldehydes 7a,b. The results are summarized in the Table 2. From the range of usual reagents used for these transformations, we first chose pyridinium chlorochromate (PCC). As can be found in literature,34 oxidations of primary alcohol to aldehydes can proceed smoothly with good yields using 1.2 mmol PCC per 1 mmol substrate in dichloromethane (DCM) at room temperature. However, the conversion of 4a under these conditions is very slow, because of its low solubility in DCM. Boiling the reaction mixture, and particularly by performing the reaction in a microwave reactor in a closed vial at 40 °C, the time required to react the substrate is significantly reduced, but at the same time decreases the yield of 7a. Higher yields of 7a were achieved when DCM was replaced with acetone, in which 4a is more soluble; we have achieved the best yield (36%) of 7a by increasing the excess of PCC and allowing the reaction to proceed for 22 hours at room temperature.
Oxidation of 4b, which is more soluble in DCM than its methyl analogue 4a, was performed in this solvent with the best yield (44%) of 7b using 1.2 mmol PCC per 1 mmol 4b and boiling of the reaction mixture, whereas the reaction was finished within 1.5 hour. When the mixture of the same initial composition was heated in a microwave reactor in a closed vial to 40 °C for 10 minutes, the yield of 7b was only slightly lower than the former. The same applies to carrying out the reaction in DCM with 1.5 mmol PCC per 1 mmol 4b at room temperature. Further increasing of the amount of PCC results in a shorter reaction time together with a reduction of yield of 7b. In contrast to oxidation of 4a to 7a, the oxidation of 4b with PCC in acetone under the same conditions furnished the aldehyde 7b with significantly lower yield.
Apart from oxidation with PCC, Swern reaction, i.e. oxidation with dimethylsulfoxide (DMSO) in the presence of oxalyl chloride and N,N-diisopropylethylamine (DIPEA), was also briefly examined using slightly modified synthetic procedure from the literature, 35 however obtained yields were unsatisfactory for both, phenyl and methyl mono-triazole derivatives 7a and 7b, respectively. While the former resulted in 33% yield of isolated product, no product was isolated in case of the latter. The main drawback of this approach is presence of hardly removable dimethyl sulfoxide that remained in our products despite the fact that they were several times washed with ice-cold water. Apparently, utilization of relatively large quantities of water also caused significant loses of target compounds that were much more obvious in the case of methyl derivative 7a. Moreover, we have experience that our 1,2,3-triazole-and quinoline-2,4-dione-based bis-heterocycles are more or less unstable in DMSO and therefore, the use of this solvent in their preparation is not always appropriate.
As the third option, oxidation of primary alcohols 4a,b with MnO 2 was further studied. Comparing the reaction parameters such as reaction times and quantities of reagents, acetone was recognized superior in comparison with dichloromethane, while transformation yields were practically the same (approx. 60%) in both cases. The findings from the above experiments were used in the oxidation of primary alcohols 5a,b and 6a-f to aldehydes 8a,b and 9a-f, respectively. In all cases, oxidation was carried out using PCC under optimum conditions for the conversion of alcohol 4b to aldehyde 7b, i.e. using 1.2 mmol PCC per 1 mmol alcohol in dichloromethane at the reflux temperature. Furthermore, the aldehydes 8a,b and 9b were prepared from the corresponding alcohols by oxidation with MnO 2 in acetone. Due to the very similar yields of aldehydes achieved with the use of one or the other reagent and the toxicity of Cr VI -containing reagents, it can be stated that MnO 2 is a more advantageous agent than PCC.
So far described oxidations of triazolyl-4-methanols to the corresponding carboxylic acids were carried out mostly with permanganate in basic medium. [36][37][38] In one case, the oxidation with a mixture of sodium chlorite and sodium hypochlorite with an addition of 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO) in phosphate buffer was patented. 39 Since basic media causes destruction of quinolinedione scaffold, the choice of reagents for the oxidation of alcohols 4a,b, 5a,b, and 6a-f is limited to those, for which the presence of no base is needed. For the transformation of these alcohols to carboxylic acids 10a,b, 11a,b, and 12a-f, we decided to try out Jones reagent (solution of CrO 3 in diluted sulfuric acid) in acetone. While this method has long been known and its use for the preparation of carboxylic acids has been described in many cases, we have found in the literature only one report 40 on its use for the preparation of triazole-4-carboxylic acids, which were intermediates in a multistep synthesis, without giving their yields and experimental details. Although at most 9 mol of CrO 3 per one mol of primary alcohol is usually used, [41][42][43] in the cases provided herein, it has been shown that the most suitable ratio is 24 mol CrO 3 per 1 mol of primary alcohol ( Table 4). The acid with methyl group in position 3 of quinolone scaffold 10a was isolated in a considerably lower yield than its phenyl ana-logue 10b probably due to its significantly higher solubility in water.
All compounds were characterized by 1 H and 13 C and, in cases of 6a-e, 7a,b, 9a-f, 10a, and 12a-f, also by 15 N NMR spectroscopy. The corresponding resonances Table 4. Oxidation of primary alcohols 4a,b, 5a,b, and 6a-f to carboxylic acids 10a,b, 11a,b, and 12a-f, respectively a .   were assigned on the basis of gradient-selected 2D NMR experiments including 1 H-1 H gs-COSY, 1 H-13 C gs-HSQC, 1 H-13 C gs-HMBC and 1 H-15 N gs-HMBC. Atoms and rings labeling scheme, which was extensively applied in the »Experimental« section is presented in Figure 2.
From the solution of 12d in deuteriochloroform originally designed to measure NMR spectra, the crystal has grown, which we have used to corroborate the structure of this compound ( Figure 3) by the single crystal X-ray structure determination. It has been found that the crystal is a solvate 12d · 2CDCl 3 . Selected bond lengths and angles are displayed in Table 5. The X-ray diffraction study has shown that the solvate 12d · 2CDCl 3 crystallizes in monoclinic P2 1 /n space group. Intermolecular hydrogen bonds of the type O-H···N are found in the crystal structure of compound 12d · 2CDCl 3 . Atom O2 acts as hydrogen bond donor and N5 of symmetry related molecule as acceptor and thus forming two dimensional chain extending along the b-axis ( Figure 4, Table 6).

Conclusions
A collection of novel 1,2,3-triazole-and quinoline-2,4(1H,3H)-dione based bis-heterocycles functional derivatives was prepared and characterized by IR, NMR and HRMS. Appropriate starting compounds with 4-(acetoxymethyl)-1H-1,2,3-triazole moiety were firstly deacetylated, and the obtained corresponding alcohols were further oxidized to aldehydes and carboxylic acids. Investigation of transformation approaches was carried out using more accessible mono-triazoles, while optimized reaction conditions were then utilized for preparation of bis-triazole counterparts in moderate to excellent yields. Synthesized derivatives could potentially possess some desirable properties or might be exploited as precursors in further transformations.
In this article we present a group of new quinoline-2,4-dione based compounds with primary alcohol, aldehyde or carboxyl functional group on 1,2,3-triazole. Even though, the chemistry applied throughout the syntheses of our final materials is pretty elemental and straightforward, we believe that we have been handling with very promising substances and therefore, in our opinion, it was worthwhile to deal with them. Prepared compounds would not only potentially exhibit some extraordinary characteristics, but may also serve as precursors in further reactions such as esterification, peptide bond formation, nucleophilic additions to formyl group etc.

Experimental
The reagents and solvents were used as obtained from the commercial sources. Column chromatography was carried out on Fluka Silica gel 60 (particle size 0.063-0.2 mm, activity acc. Brockmann and Schodder 2-3). Melting points were determined on the microscope hot stage, Kofler, PolyTherm, manufacturer Helmut Hund GmbH, Wetzlar and are uncorrected. TLC was carried out on pre-coated TLC sheets ALUGRAM ® SIL G/UV 254 for TLC, MACHEREY-NAGEL. NMR spectra were recorded with a Bruker Avance III 500 MHz NMR instrument operating at 500 MHz ( 1 H), 126 MHz ( 13 C) and 51 MHz ( 15 N) at 300 K, or JEOL ECZ400R/S3 instrument operating at 400 MHz ( 1 H) and 100 MHz ( 13 C). Proton spectra were referenced to TMS as internal standard, in some cases to the residual signal of DMSO-d 5 (at δ 2.50 ppm) or CHCl 3 (at δ 7.26 ppm). Carbon chemical shifts were determined relative to the 13 C signal of DMSO-d 6 (39.52 ppm) or CDCl 3 (77.16 ppm). 15 N chemical shifts were extracted from 1 H-15 N gs-HMBC spectra (with 20 Hz digital resolution in the indirect dimension and the parameters adjusted for a long-range 1 H-15 N coupling constant of 5 Hz) determined with respect to external nitromethane and are corrected to external ammonia by addition of 380.5 ppm. Nitrogen chemical shifts are reported to one decimal place as measured of the spectrum, however, the data should not be considered to be more accurate than ±0.5 ppm because of the digital resolution limits of the experiment. Chemical shifts are given on the δ scale (ppm). Coupling constants (J) are given in Hz. Multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) or br (broadened). Infrared spectra were recorded on FT-IR spectrometer Alpha (Bruker Optik GmbH Ettlingen, Germany) using samples in potassium bromide disks and only the strongest/structurally most important peaks are listed. HRMS spectra were recorded with Agilent 6224 Accurate Mass TOF LC/MS system with electrospray ionization (ESI).
X-ray crystallography. The molecular structure of compound 12d was determined by single-crystal X-ray diffraction methods. Crystallographic data and refinement details are given in Table 7. Diffraction data for 12d were collected at room temperature with Agilent SuperNova dual source diffractometer using an Atlas detector and equipped with mirror-monochromated MoKα radiation (λ = 0.71073 Å). The data were processed by using CrysAlis PRO.44 All the structures were solved using SHELXS-9745 and refined against F 2 on all data by full-matrix least-squares with SHELXL-2016. 46 All non-hydrogen atoms were refined anisotropically. The C3 and C21 bonded hydrogen atoms were located in a difference map and refined with the distance restraints (DFIX) with C-H = 0.98 Å and with U iso (H) = 1.2U eq (C). All other hydrogen atoms were included in the model at geometrically calculated positions and refined using a riding model. The crystal structure 12d contains deuterated solvent molecules (CDCl 3 ). The D and H atoms are both treated as hydrogens but the SFAC instruction for D enables the formula weight and density to be calculated correctly. The C29 and C30 bonded deuterium atoms were located in a  2 ]/(n/p} 1/2 where n is the number of reflections and p is the total number of parameters refined. difference map and refined with the distance restraints (DFIX) with C-D = 0.98 Å and with U iso (D) = 1.2U eq (C).
CCDC 1892717 (for 12d · 2CDCl 3 ) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif.

3-(4-(
General procedure for the preparation of aldehydes 7a,b using Swern reaction. To a dry 25 mL evacuated flask, oxalyl chloride (155 μL; 1.8 mmol) and dry tetrahydrofurane (THF) were added. The flask was equipped with nitrogen gas inlet and cooled to -70 °C using dry ice-ethanol bath. Afterwards, DMSO (280 μL) was added dropwise and obtained solution was stirred for 60 minutes, keeping the temperature bellow -65 °C. Then, suitable mono-triazole alcohol 4 (1.5 mmol) dissolved in dry dichloromethane or acetone (11 mL) was added and stirring was continued for 90 minutes. Finally, after addition of DIPEA (1.275 mL; 7.32 mmol), the content of the flask was stirred for additional 2 hours and tempered to the lab temperature. The reaction mixture was diluted with distilled water (10 mL) and extracted with dichloromethane (3x 20 mL). Combined organic phases were washed with ice-cold water (4x 20 mL), dried over anhydrous Na 2 SO 4 , filtered and volatile components were evaporated in vacuo. Obtained oily crude product was purified on silica-gel column, using 38% ethyl acetate in petroleum ether as mobile phase. To that way gained oily product, diethyl ether was added and it was cooled to -20 °C to provide solid compound that was filtered through the sintered glass filter and dried at 50 °C. For the yields of products see Table 2.