Heterocyclic Analogues of Xanthone and Xanthione. 1H-Pyrano[2,3-c:6,5-c]dipyrazol-4(7H)-ones and Thiones: Synthesis and NMR Data

The synthesis of the title compounds is described. Reaction of 1-substituted 2-pyrazolin-5-ones with 5-chloro-1-phenyl-1H-pyrazole-4-carbonyl chloride or 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbonyl chloride, respectively, using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-heteroaroylpyrazol-5-ols, which were cyclized into 1H-pyrano[2,3-c:6,5-c]dipyrazol-4(7H)-ones by treatment with K2CO3/DMF. The latter were converted into the corresponding thiones upon reaction with Lawesson’s reagent. Detailed NMR spectroscopic investigations (1H, 13C, 15N) of the ring systems and their precursors are presented.


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literature. In view of this fact synthetic derivatives of xanthones are attractive compounds for medicinal chemists. As a result analogues in which one or both benzene rings of the parent xanthone system had been replaced by heteroaromatic moieties were also studied. As a representative example of these compounds the anti-ulcer agent amlexanox ( Figure 1) may be cited [8].

Chemistry
Synthesis of the target compounds 4 was accomplished via the sequence shown in Scheme 2. 2-Pyrazolin-5-ones 1 are either commercially available or can be easily prepared according to known methods [21]. Acid chlorides 2, which can be considered as the key synthons in the approach presented, were prepared as follows: Vilsmaier-Haak formylation [22] of pyrazolones 1a and 1b, respectively, gave the 5-chloropyrazole-4-carbaldehydes 6, which were oxidized to the corresponding carboxylic acids 7 by treatment with potassium permanganate [23]. Transformation of acids 7 into the appropriate acid chlorides 2 was accomplished with thionyl chloride in refluxing toluene [9,11,12]. Compounds 2 were always freshly prepared before reacting them with pyrazolones 1; treatment of 7a,b with dry ethanol led to esters 9a,b [24] (Scheme 2).
Different pyrazolones 1a-e were reacted with acid chlorides 2a,b using calcium hydroxide in boiling dioxane [17] to afford the 4-pyrazoloylpyrazol-5-ols 3a-g (Scheme 2). However, in two cases (the reactions of 1c with 2b, and 1d with 2b, respectively) the corresponding compounds of type 3 were not obtained, and instead, the isomeric esters 8a and 8b resulting from O-aroylation of 1c and 1d were isolated as the major products from the reaction mixtures. Their structures could be easily derived from the 1 H-NMR spectra considering the characteristic singlet signal due to pyrazole H-4 at δ 6.04 (8a) and δ 6.30 ppm (8b). Attempts to convert compounds 8 into their corresponding 4-aroyl congeners 3 failed. Finally, cyclization of intermediates 3 under standard conditions (K 2 CO 3 in DMF) [25] gave the target tricycles 4a,b and 4d-g in good yields. Treatment of the latter with Lawesson's reagent [26][27][28] in refluxing toluene smoothly afforded the corresponding thiones 5a,b and 5d-g. It should be mentioned that compounds 4d and 5d have already been described by Sarenko and coworkers [29]. Finally, the N-7 unsubstituted compounds 4x and 5x were prepared by treatment of the corresponding N7-PMB-protected congeners 4f and 5f, respectively, with trifluoroacetic acid at 70 ºC [9,12] (Scheme 3).

NMR Spectroscopic Investigations
The NMR data of compounds 2, 3, 6-8 are given in the Experimental, whereas those of title compounds 4 and 5 are collected in Tables 2-5. Unequivocal assignment of signals was carried out by the combined application of standard NMR spectroscopic techniques such as 1 H-coupled 13 C-NMR spectra, APT, HMQC, gs-HSQC, gs-HMBC, COSY, TOCSY, NOESY and NOE-difference spectroscopy [30]. Moreover, in a few cases experiments with selective excitation (DANTE) of certain 1 H-resonances were performed, such as long-range INEPT [31] and 2D(δ,J) long-range INEPT [32], the latter experiments were indispensable for the unambiguous mapping of long-range 13 C, 1 H coupling constants. Reliable and unambiguously assigned chemical shift data such as those presented here can be considered as important reference material for NMR prediction programs, such as CSEARCH [33]/NMRPREDICT [34] and ACD/C + H predictor [35] -programs which have become very popular in the last few years, particularly for predicting 13 C-NMR chemical shifts. 4-Aroylpyrazol-5-ols 3 in each case contain two different pyrazole units which exhibit characteristic differences regarding their chemical shift data. The 5-OH group in the hydroxypyrazole moiety leads to a strong polarization of the C4−C5 bond resulting in small chemical shifts for pyrazole C-4 (103−106 ppm) and large ones for pyrazole C-5 (159−161 ppm). These differences are significantly smaller in the 5-chloropyrazole unit with δ pyrazole C-4 having 117−119 ppm and pyrazole C-5 127−131 ppm. In congeners carrying phenyl substituents at both pyrazole N-1's (compounds 3a-d) an explicit difference regarding the resonances due to Ph C-2,6 is quite obvious (δ ~121 ppm in the 1-Ph-pyrazol-5-ol unit, δ ~125.5 ppm in the 1-Ph-5-Cl-pyrazole unit). Moreover, also the 15 N-NMR chemical shifts in the mentioned pyrazole moieties differ markedly, both nitrogen atoms of the hydroxypyrazole system (for instance 3a: N-1 −185.2 ppm, N-2 −97.9 ppm) show distinctly smaller chemical shifts than the corresponding ones in the chloropyrazole system (N-1 −159.9 ppm, N-2 −72.4 ppm). The C=O resonance in compounds 3 is located in the range from 181−184 ppm. In Figure 2, 1 H, 13 C and 15 N-NMR chemical shift data are presented for 3a which can be considered as a typical example.   In Figure 2, the chemical shift data for the corresponding tricycles 4a and 5a are also depicted, which − exemplarily -permit one to follow the changes when switching from the central pyran-4-one (4a) to a pyran-4-thione (5a) system. The transformation 4a → 5a leaves the 1 H-and 13 C-NMR chemical shifts due to the phenyl ring nearly unchanged; δ (N-1), δ (N-2) and δ (C-3) are also only slightly affected. However, in 4a a pronounced 'push-pull situation' is on hand which leads to a strong polarization of the pyrane C=C bond resulting in a large chemical shift for C7a/C8a (δ 151.3 ppm) and a small for C3a/C4a (δ 108.8 ppm). In 5a this effect is much less pronounced leading to an upfield shift for C7a/C8a (δ 145.5 ppm) and a marked downfield shift for C3a/C4a (δ 117.8 ppm) compared to the appropriate shifts in 4a. Expectedly, C-4 suffers a distinct downfield shift (169.7 ppm → 192.1 ppm) when switching from 4a to 5a, the difference of 22.4 ppm is comparable with corresponding values found in related systems [36].
Whereas assignment of signals in most cases is easy, the discrimination of signals due to N1-phenyl and N7-phenyl in 'asymmetric' compounds 4b and 5b is not trivial. Ultimately, this assignment is possible considering the correlations found in the 15 N, 1 H-HMBC spectra. Thus, for instance, in compound 5b the singlet signal due to H-5 (δ 8.32 ppm) exhibits a correlation to the 15 N signal with δ -188.0 ppm, which consecutively must be that of N-7. The latter is also connected to the Ph H-2,6 resonance at δ 7.82 ppm, which accordingly has to be part of the N-7-phenyl system and thus can be unambiguously distinguished from Ph H-2,6 of the N1-phenyl moiety (δ 7.81 ppm). On basis of COSY (TOCSY), HSQC and HMBC experiments then the unequivocal assignment of all proton and carbon signals due to N1-Ph and N7-Ph is possible.

General
Melting points were determined on a Reichert-Kofler hot-stage microscope and are uncorrected. Mass spectra were obtained on a Shimadzu QP 1000 instrument (EI, 70 eV), a Finnigan MAT 8230 instrument (EI, 70 eV, HRMS), and a Finnigan MAT 900S instrument (ESI, 4 kV, MeOHacetonitrile). IR spectra (KBr unless otherwise stated) were recorded on a Perkin-Elmer FT-IR 1605 spectrophotometer. Elemental analyses (C, H, N and S) were performed at the Microanalytical Laboratory, University of Vienna, and were in good agreement (±0.4%) with the calculated values. 1 Hand 13 C-NMR spectra were recorded on a Varian UnityPlus 300 spectrometer at 28 ºC (299.95 MHz for 1 H, 75.43 MHz for 13 C) or on a Bruker Avance 500 spectrometer at 293 K (500.13 MHz for 1 H, 125.77 MHz for 13 C). The center of the solvent signal was used as an internal standard, which was related to TMS with δ 7.26 ppm ( 1 H, CDCl 3 ), δ 2.49 ppm ( 1 H, DMSO-d 6 ), δ 77.0 ppm ( 13 C, CDCl 3 ) and δ 39.5 ppm ( 13 C, DMSO-d 6 ). 15 N-NMR spectra (50.68 MHz) were obtained on a Bruker Avance 500 spectrometer with a 'directly' detecting broadband observe probe (BBFO) and were referenced against external nitromethane. The digital resolution was 0.25 Hz/data point in the 1 H spectra and 0.4 Hz/data point in the 13 C-NMR spectra. Systematic names were generated with ACD/Name [40] according to the IUPAC recommendations and were checked manually [41]. For chromatographic separations, Kieselgel 60 (70-230 mesh, Merck) was used.

General procedure for the synthesis of the carbaldehydes 6a and 6b
Under anhydrous conditions, POCl 3 (53.65 g, 32.5 mL, 350 mmol) was carefully added dropwise to dry DMF (11.70 g, 12.3 mL, 160 mmol) under cooling. Then pyrazolone 1 (50 mmol) was added and the mixture was heated to reflux for 2 hours. The reaction mixture was subsequently cooled to room temperature and the darkly coloured solution was poured onto ice water (approximately 300 mL) while stirring. After 30 minutes the precipitate formed was filtered off, washed with H 2 O and dried.

General procedure for the synthesis of the acid chlorides 2a and 2b
A suspension of the accordant carboxylic acid 7 (2 mmol) in toluene (10 mL), excess SOCl 2 (10 mL) and 1 droplet of DMF was refluxed for 3 h. Then toluene and excess SOCl 2 were distilled off. More toluene was added and the solvent was distilled off again. The remaining acid chloride was used immediately. A solution of the appropriate acid chloride 2 (5 mmol) in dry 1,4-dioxane (5 mL) was added dropwise to a suspension of pyrazolone (1a-e, 5 mmol) and Ca(OH) 2 (10 mmol) in dry 1,4-dioxane (5 mL). The reaction mixture was heated to reflux for 3 h under anhydrous conditions. After cooling to room temperature the mixture was treated with 2 N HCl (20 mL), stirred for 30 min and afterwards H 2 O (20 mL) was added. Then the products were filtered off, washed with H 2 O and recrystallized. Spectroscopic and analytical data of 3a-g and 8a-b are summarized in Table 1.

1-(4-Methoxybenzyl)-1H-pyrazol-5-yl 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (8b).
Starting from pyrazolone 1d (1.021 g, 5 mmol) and acid chloride 2b (1.28 g, 5 mmol) 1.08 g (51%) of compound 8b were obtained as colorless crystals of m.p. 116 ºC (EtOH).       3.2.6. Cyclization of 4-Aroylpyrazolones 3a-g: General procedure for the synthesis of 4a-b, 4d-g Under anhydrous conditions, K 2 CO 3 (138 mg, 1 mmol) was added to a solution of the appropriate type 3 compound (1 mmol) in dry DMF (10 mL), then the mixture was heated to reflux for 2 h. After evaporation of the solvent, 20 mL of H 2 O were added to the residue. The precipitate was filtered off, washed with water and recrystallized from EtOH. NMR data of the products are given in Tables 2-5. 3.2.7. General procedure for the synthesis of 5a-b and 5d-g Lawesson's Reagent (202 mg, 0.5 mmol) was added to a solution of the appropriate oxo compound 4 in 15 mL of toluene and the mixture was heated to reflux for approx. 14 h. After cooling, the precipitate was filtered off and recrystallized from EtOH. In case of 5b no precipitate was formed, here the solvent was evaporated and the residue was subjected to column chromatography (silica gel, mobile phase CH 2 Cl 2 :MeOH/9:1) in order to obtain the colored thione which was crystallized from EtOH for analytical purposes. NMR data of the products are given in Tables 2-5.  Under anhydrous conditions, a solution of the PMB-substituted congener 4f or 5f (0.5 mmol) and trifluoroacetic acid (TFA, 1.43 g, 12.5 mmol) was heated to reflux overnight. After removal of excess TFA under reduced pressure the residue was stored over solid KOH. Then ice-cold diethyl etheracetone (3:1) was added. The precipitate was filtered off and washed with cold diethyl ether-acetone. NMR data of the products are given in Tables 2-5 1-Phenyl-1H-pyrano [2,3- 4a-b, 4d-g, 5a-b, 5d-g, 4x and 5x (δ in ppm, solvents as listed in Table 2).  Table 4. Selected 13 C, 1 H spin coupling constants of 4a-b, 4d-g, 5a-b, 5d-g, 4x and 5x (Hz, solvents as listed in Table 2). Table 5. 15 N-NMR chemical shifts of investigated compounds (δ in ppm, solvents as listed in Table 2). 3.2.9. General procedure for the synthesis of 9a and 9b According to a known procedure [24], to a solution of the corresponding carboxylic acid 7 (5 mmol) in absolute ethanol (30 mL), H 2 SO 4 (2 mL) was added and the mixture was refluxed for 8 h. After the reaction mixture was concentrated in vacuo, the residue was neutralized with a saturated solution of NaHCO 3 and then extracted with dichloromethane (3 × 15 mL). Organic layers were combined and dried over sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography (silica gel, mobile phase CH 2 Cl 2 :MeOH/9:1).