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Article

A Convenient Approach to Heterocyclic Building Blocks: Synthesis of Novel Ring Systems Containing a [5,6]Pyrano[2,3-c]pyrazol-4(1H)-one Moiety

by
Gernot Eller
* and
Wolfgang Holzer
Department of Drug and Natural Product Synthesis, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
*
Author to whom correspondence should be addressed.
Molecules 2007, 12(1), 60-73; https://doi.org/10.3390/12010060
Submission received: 15 January 2007 / Revised: 24 January 2007 / Accepted: 24 January 2007 / Published: 26 January 2007
Browse Figures
Versions Notes

Abstract

:
Starting from commercially available educts, a straightforward synthetic route to new heterocyclic building blocks is exemplified with the one- or two-step synthesis of tri-, tetra-, or pentacyclic ring systems. Representatives of the following novel ring systems are prepared from 3-methyl-1-phenyl-2-pyrazolin-5-one and the corresponding o-halo-arenecarbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane: pyrimidino[4',5':5,6]pyrano[2,3-c]pyrazol-4(1H)-one, thieno[3',2':5,6]pyrano[2,3c]pyrazol- 4-(1H)-one, thieno[3',4':5,6]pyrano[2,3-c]pyrazol-4(1H)-one, thieno[3'',2'':4',5']thieno­[2',3':5,6]-pyrano[2,3-c]pyrazol-4(1H)-one, [1,3]dioxolo[5',6'][1]benzothieno[2',3':5,6]­pyrano-[2,3-c]- pyrazol-4(1H)-one, pyridazino[4',3':5,6]pyrano[2,3-c]pyrazol-4(1H)-one and pyrazolo-[4'',3'':5',6']pyrido[3',4':5,6]pyrano[2,3-c]pyrazol-4(1H)-one. While the latter two ring systems are directly obtained due to a spontaneous intramolecular substitution reaction, in the other reactions uncyclised 4-aroylpyrazol-5-ols are produced, which are cyclised into the target heterocycles in a subsequent synthetic step (i.e. treatment with NaH in DMF). Detailed NMR spectroscopic investigations (1H-, 13C-, 15N-) with the obtained compounds were undertaken to unambiguously prove the new structures.

Introduction

The search for biologically active compounds is the driving force in pharmaceutical synthesis. Since the majority of new molecules entering clinical studies contains at least one heterocyclic moiety – predominantly N-heterocyclic ones [1] – the modification of these ring systems plays an important role during drug development [2,3]. Thus, there is always a specific need for novel heterocyclic ring systems, both for finding new hit structures and in optimisation of lead compounds. Although theoretically unlimited, in practical terms and due to technical and economical reasons, only a very limited number of heterocycles is available for medicinal chemistry today.
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Figure 1.
Figure 1.
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Our own interest in new and easily accessible heterocyclic building blocks stems from our ongoing research on xanthone (= dibenzo-γ-pyrone) derivatives, in which one of the benzene rings is replaced with a pyrazole nucleus and the other with a different heterocyclic moiety [4,5,6]. These interesting substructures occur in several bioactive compounds, such as in the anti-ulcer drug, amlexanox (Aphthasol™) [7,8] or in the A2-subtype selective adenosine receptor antagonist A [9] (Figure 1). Consequently we investigated several synthetic strategies to facilitate alteration of this biologically interesting scaffold. While our primary research was based on synthetic approaches for the convenient variation of the substituents at the pyrazole core (in particular those of positions C-3, N-1 and N-2) [10,11], we turned our interest to the modification of the molecule's skeleton as well as the possibility of introducing substituents at other positions. The combination of these approaches would obviously allow access to specifically customised molecules. Nevertheless, only a few skeletons – mainly tricyclic ones like the possible four pyridines [4] – have been reported as successfully attempted up to the present.

Results and Discussion

The purpose of this study is to report the convenient one- or two-step synthesis of novel heterocyclic ring systems (Table 1) containing a [5,6]pyrano[2,3-c]pyrazol-4(1H)-one moiety starting from commercially available educts. Thus, 2-pyrazolin-5-one 1 (a tautomer of 5-hydroxypyrazole [12]) was reacted with the corresponding o-haloarenecarbonyl chlorides 2b–8b (Figure 2) in the presence of excess calcium hydroxide in boiling 1,4-dioxane (the 'Jensen' method [13]) to affect the selective acylation at the pyrazole C-4. However, the target compounds 9 and 10 were directly obtained in the reaction of the acid chlorides 2b and 3b with pyrazolone 1, without isolation of the expected 4-aroylpyrazol-5-ols (Scheme 1).
Molecules 12 00060 g002 550
Figure 2. Structure of o-haloarenecarbonyl chlorides 2b–8b.
Figure 2. Structure of o-haloarenecarbonyl chlorides 2b–8b.
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Obviously, spontaneous intramolecular cyclisation did occur (only) in these two cases, leading to formation of two new bonds (C–C and O–C, respectively) in a single reaction step in these molecules. This fact could be correlated with the activity towards nucleophilc aromatic substitution of the leaving halogen in the presumptive intermediates 21 and 22 (Figure 3). In electron-rich aromatic compounds (which are known to be less reactive towards nucleophilic aromatic substitutions) such as thiophene derivatives 17–20 or even in the pyrimidine example 16 (where the halogen atom is situated meta to the activating N atom and hence the least active position in such pyridines), no cyclisation was observed. However, ring closure occurred spontaneously in the reactions of the acid chlorides 2b and 3b, in which the halogen was situated ortho or para to the activating N atom. This behaviour is in full agreement with the observations made in cyclisation reactions leading to different pyridine[5,6]-pyrano[2,3-c]pyrazol4(1H)-ones [4].
Molecules 12 00060 g006 550
Scheme 1. Synthesis of the title compounds.
Scheme 1. Synthesis of the title compounds.
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When the uncyclised intermediates were isolated, the transformation into the target ring systems was achieved by treatment of 4-aroylpyrazol-5-ols 16–20 with sodium hydride in refluxing dimethylformamide.
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Figure 3. Intermediate 4-Aroylpyrazol-5-ols 16–22.
Figure 3. Intermediate 4-Aroylpyrazol-5-ols 16–22.
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NMR spectroscopy

Recently, assignment of NMR signals (mainly 13C-NMR lines) using prediction programs [14] such as CSEARCH [15] or ACD/C+H NMR Predictor [16] has become increasingly popular. However, the quality of such empirical predictions strongly depends on the availability in the corresponding databases of reliable material data from related structures. Thus, in cases where insufficient (or low quality) data is available for the description of a specific chemical environment, the prediction results are poor. The latter seems to be the case for many condensed heterocyclic systems containing few protons. This lack of high quality data provided the motivation for us to perform detailed NMR spectroscopic investigations of all novel compounds prepared and also their precursors. Full and unambiguous assignment for all proton (1H-), carbon (13C-), and nitrogen (15N-) resonances could be achieved by the combined application of different NMR spectroscopic techniques [17] such as NOESY [18], NOE-difference experiments (1H{1H} [18] as well as 13C{1H} [18,19,20]), fully 1H-coupled 13C-NMR spectra, APT, HMQC, gs-HMSC, and gs-HMBC spectra. The assignments were also be facilitated by experiments with selective excitation such as 1D-TOCSY [21], 1D-HETCOR [22], and selective long-range INEPT experiments [23]. 13C,1H spin coupling constants were also determined and unequivocally assigned by two-dimensional (δ, J) long-range INEPT spectra with selective excitation [24]. The 15N-NMR spectra were mainly recorded using the gradient selected, sensitivity enhanced HMBC sequence [25].
The assignment of the numerous lines due to quaternary carbon atoms has not been a trivial task. For instance, in target compounds 9–15, the chemical shifts of the two carbon atoms directly attached to the pyran oxygen atom often closely resemble each other. Despite this fact, an unequivocal distinction was possible on basis of the 1H-coupled 13C-NMR spectra. The signal of the carbon atom located between pyrazole N-1 and the pyran oxygen always appears as a singlet, whereas the signal of the opposite pyran O–C atom is split by couplings to protons belonging to the system condensed on the ‘right’ side of the pyran ring. In compound 14 this diagnostic coupling is small (3JC8b,H8=1.0 Hz) and emerges only after pronounced resolution enhancement. Discrimination of C-5a vs. C-8a in 14, C-5a vs. C-10a in 15, and C-5 vs. C-7 in 13 is based on the upfield shift of the latter signal in each pair due to the influence of the pyran oxygen atom. In the fused pyrimidine derivative 11 the discrimination of the lines due to C-4a and C-8a (144.4 ppm, 146.0 ppm) is not possible considering the 1H-coupled 13C-NMR spectrum, since both signals show a 3 Hz splitting due to coupling with H-8. Here, unambiguous assignment of C-8a was achieved via a heteronuclear 13C{1H} NOE-difference experiment. Irradiation of the H-8 transition only enhanced the signal of the spatially close C-8a whereas the line of the more distant C-4a remained unaffected (Figure 3).
Molecules 12 00060 g005 550
Figure 3. Unambiguous 13C-NMR signal assignment of C-4a and C-8 in compound 11 in CDCl3: 13C{1H}-NOE on C-8 and C-8a upon selective irradiation of H-8.
Figure 3. Unambiguous 13C-NMR signal assignment of C-4a and C-8 in compound 11 in CDCl3: 13C{1H}-NOE on C-8 and C-8a upon selective irradiation of H-8.
Molecules 12 00060 g005
A similar approach was used to support the discrimination of the signals due to C-3a and C-6a in 4-acylpyrazolone 19 (enhancement of the C-3a signal after irradiation of H-4). In the latter compound, the signal of H-4 (attached to the carbon atom in β-position to the thiophene S-atom 6) can be simply distinguished from that of H-5 (attached to C-5, in α-position to S-6) considering the larger 1J coupling constants in the thiophene α-C,H fragment (in 19: 1JC5,H5=189.3 Hz > 1JC4,H4=173.3 Hz). This criterion was also employed to achieve correct assignments in compounds 7b, 12, 14, and 17.
In most cases, assignment of 15N-NMR signals was easily made on basis of chemical shift considerations together with correlations emerging from the gs-HMBC spectra. As an illustrative example, the 15N,1H HMBC spectrum of compound 10 is displayed in Figure 4.
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Figure 4. 15N,1H-HMBC spectrum of compound 10 in CDCl3.
Figure 4. 15N,1H-HMBC spectrum of compound 10 in CDCl3.
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Table
Table 1. 1H-, 13C-, and 15N-NMR chemical shifts as well as selected 1H,1H and 13C,1H Spin-Coupling Constants of the Novel Ring Systems 9–15.
Table 1. 1H-, 13C-, and 15N-NMR chemical shifts as well as selected 1H,1H and 13C,1H Spin-Coupling Constants of the Novel Ring Systems 9–15.
EntryStructureNMR data
9 Molecules 12 00060 i0011H-NMR (500 MHz, CDCl3) δ: 2.66 (3H, s, Me), 7.43 (1H, m, Ph H-4), 7.56 (2H, m, Ph H-3,5), 7.92 (2H, m, Ph H-2,6), 8.36 (1H, s, H-5).
13C-NMR (125 MHz, CDCl3) δ: 14.0 (Me, 1J=129.7 Hz), 105.1 (C-3a, 3JC3,Me=2.8 Hz), 121.6 (Ph C-2,6), 122.7 (C-4a, 2JC4a,H5=1.3 Hz), 126.9 (C-5, 1J=179.0 Hz), 128.3 (Ph C-4), 129.7 (Ph C-3,5), 136.1 (Ph C-1), 148.7 (C-3, 2JC3,Me=7.2 Hz), 152.2 (C-9a), 155.5 (C-6, 2JC6,H5=0.9 Hz), 160.3 (C-8a, 3JC8a,H5=7.1 Hz), 169.7 (C-4, 3JC4,H5=4.3 Hz).
15N-NMR (50 MHz, CDCl3) δ: −189.5 (N-1), −89.6 (N-2), −8.6 (N-8), 19.9 (N-7).
10 Molecules 12 00060 i0021H-NMR (300 MHz, CDCl3) δ: 2.67 (3H, s, 7-Me), 2.74 (3H, s, 1-Me), 4.11 (3H, s, NMe), 7.42 (1H, m, Ph H-4), 7.56 (2H, m, Ph H-3,5), 7.87 (2H, m, Ph H-2,6), 9.30 (1H, s, H-5). 1H-NMR (300 MHz, DMSO-d6) δ: 2.59 (3H, s, 7-Me), 2.68 (3H, s, 1-Me), 4.05 (3H, s, NMe), 7.50 (1H, m, Ph H-4), 7.65 (2H, m, Ph H-3,5), 7.94 (2H, m, Ph H-2,6), 9.17 (1H, s, H-5).
13C-NMR (75 MHz, CDCl3) δ: 14.0 (7-Me, 1J=129.4 Hz), 14.3 (1-Me, 1J=128.8 Hz), 34.1 (NMe, 1J=140.9 Hz), 103.3 (C-10b, 3JC10b,1Me=3.0 Hz, 4JC10b,H5=1.2 Hz), 105.8 (C-6a, 3JC6a,7Me=2.8 Hz), 111.8 (C-5a, 2JC5a,H5=7.9 Hz), 121.3 (Ph C-2,6), 127.9 (Ph C-4), 129.5 (Ph C-3,5), 136.6 (Ph C-1), 140.4 (C-1, 2JC1,1Me=7.2 Hz), 148.3 (C-7, 2JC7,7Me=7.2 Hz), 149.9 (C-5, 1J=186.2 Hz), 151.6 (C-9a), 154.4 (C-3a, 3JC3a,NMe=2.1 Hz, 3JC3a,H5=15.5 Hz), 155.5 (C-10a, 3JC10a,H5=8.3 Hz), 172.6 (C-6, 3JC6,H5=2.2 Hz).
15N-NMR (50 MHz, CDCl3) δ: −202.4 (N-3), −191.6 (N-9), −119.8 (N-4), −94.8 (N-8), −66.8 (N-2).
11 Molecules 12 00060 i0031H-NMR (300 MHz, CDCl3) δ: 2.68 (3H, s, 3-Me), 2.68 (3H, s, SMe), 7.42 (1H, m, Ph H-4), 7.55 (2H, m, Ph H-3,5), 7.82 (2H, m, Ph H-2,6), 8.96 (1H, s, H-8).
13C-NMR (75 MHz, CDCl3) δ: 14.1 (3-Me, 1J=129.6 Hz), 14.8 (SMe, 1J=141.8 Hz), 107.8 (C-3a, 3JC3a,3Me=2.8 Hz), 121.5 (Ph C-2,6), 128.0 (Ph C-4), 129.6 (Ph C-3,5), 136.4 (Ph C-1), 144.4 (C-4a, 3JC4a,H8=3.0 Hz), 146.0 (C-8a, 2JC8a,H8=3.0 Hz), 148.8 (C-3, 2JC3,3Me=7.2 Hz), 150.1 (C-8, 1J=187.4 Hz), 151.5 (C-9a), 170.2 (C-6, 3JC6,SMe=4.7 Hz, 3JC6,H8=12.8 Hz), 170.7 (C-4, 4JC4,H8=2.0 Hz).
15N-NMR (50 MHz, CDCl3) δ: −191.9 (N-1), −108.9 (N-5), −91.1 (N-2), −80.2 (N-7).
12 Molecules 12 00060 i0041H-NMR (300 MHz, CDCl3) δ: 2.68 (3H, s, Me), 6.95 (1H, d, 3JH6,H5=5.9 Hz, H-6), 7.39 (1H, m, Ph H-4), 7.42 (1H, d, 3JH5,H6=5.9 Hz, H-5), 7.42 (2H, m, Ph H-3,5), 7.81 (2H, m, Ph H-2,6).
13C-NMR (75 MHz, CDCl3) δ: 14.1 (Me, 1J=129.3 Hz), 106.5 (C-3a, 3JC3a,Me=2.7 Hz), 116.2 (C-6, 1J=191.2 Hz, 2JC6,H5=6.5 Hz), 121.3 (Ph C-2,6), 121.4 (C-5, 1J=175.0 Hz, 2JC5,H6=3.5 Hz), 126.0 (C-4a, 2JC4a,H5=4.3 Hz, 3JC4a,H6=8.1 Hz), 127.6 (Ph C-4), 129.5 (Ph C-3,5), 136.8 (Ph C-1), 147.8 (C-3, 2JC3,Me=7.1 Hz), 153.8 (C-8a), 163.7 (C-7a, 3JC7a,H6=8.7 Hz, 3JC7a,H5=11.4 Hz), 171.0 (C-4).
15N-NMR (50 MHz, CDCl3) δ: −193.4 (N-1), −94.8 (N-2).
13 Molecules 12 00060 i0051H-NMR (500 MHz, CDCl3) δ: 2.70 (3H, s, Me), 7.15 (1H, d, 3JH7,H5=3.3 Hz, H-7), 7.40 (1H, m, Ph H-4), 7.54 (2H, m, Ph H-3,5), 7.85 (2H, m, Ph H-2,6), 8.12 (1H, d, 3JH5,H7=3.3 Hz, H-5).
13C-NMR (125 MHz, CDCl3) δ: 14.2 (Me, 1J=129.3 Hz), 104.8 (C-3a, 3JC3a,Me=2.5 Hz), 105.7 (C-7, 1J=190.0 Hz, 3JC7,H5=4.3 Hz), 121.6 (Ph C-2,6), 126.3 (C-5, 1J=192.2 Hz, 3JC5,H7=5.9 Hz), 127.5 (Ph C-4), 129.4 (Ph C-3,5), 129.5 (C-4a), 137.0 (Ph C-1), 148.7 (C-3, 2JC3,Me=7.1 Hz), 151.4 (C-7a, 3JC7a,H5=11.2 Hz), 154.7 (C-8a), 171.2 (C-4, 3JC4,H5=2.1 Hz).
14 Molecules 12 00060 i0061H-NMR (300 MHz, CDCl3) δ: 2.68 (3H, s, Me), 7.40 (1H, d, 3JH8,H7=5.4 Hz, H-8), 7.41 (1H, m, Ph H-4), 7.47 (1H, d, 3JH7,H8=5.4 Hz, H-7), 7.56 (2H, m, Ph H-3,5), 7.87 (2H, m, Ph H-2,6).
13C-NMR (75 MHz, CDCl3) δ: 14.0 (Me, 1J=129.3 Hz), 105.8 (C-3a, 3JC3a,Me=2.8 Hz), 117.9 (C-8, 1J=173.9 Hz, 2JC8,H7=4.1 Hz), 121.2 (Ph C-2,6), 127.0 (C-4a, 5JC4a,H7=0.8 Hz), 127.5 (Ph C-4), 129.5 (Ph C-3,5), 130.2 (C-7, 1J=188.4 Hz, 2JC7,H8=6.9 Hz), 134.9 (C-8a, 2JC8a,H8=5.5 Hz, 3JC8a,H7=10.5 Hz), 137.1 (Ph C-1), 142.6 (C-5a, 3JC5a,H7=7.7 Hz, 3JC5a,H8=9.6 Hz), 147.2 (C-3, 2JC3,Me=7.1 Hz), 147.5 (C-8b, 3JC8b,H8=1.0 Hz, 4JC8b,H7=0.8 Hz), 153.1 (C-9a), 170.2 (C-4).
15N-NMR (50 MHz, CDCl3) δ: −193.2 (N-1), −93.8 (N-2).
15 Molecules 12 00060 i0071H-NMR (500 MHz, CDCl3) δ: 2.71 (3H, s, Me), 6.13 (2H, s, H-8), 7.24 (1H, s, H-6), 7.34 (1H, s, H-10), 7.43 (1H, m, Ph H-4), 7.59 (2H, m, Ph H-3,5), 7.91 (2H, m, Ph H-2,6).
13C-NMR (125 MHz, CDCl3) δ: 14.1 (Me, 1J=129.3 Hz), 99.6 (C-10, 1J=168.0 Hz, 4JC10,H6=1.3 Hz), 102.3 (C-8, 1J=174.9 Hz), 102.9 (C-6, 1J=168.7 Hz, 4JC6,H10=1.3 Hz), 106.2 (C-3a, 3JC3a,Me=2.7 Hz), 121.2 (Ph C-2,6), 122.4 (C-4a), 122.5 (C-10a, 3JC10a,H6=6.3 Hz), 127.5 (Ph C-4), 129.6 (Ph C-3,5), 134.7 (C-5a, 2JC5a,H6=1.5 Hz, 3JC5a,H10=7.7 Hz), 137.1 (Ph C-1), 147.3 (C-3, 2JC3,Me=7.1 Hz), 147.7 (C-9a, 2JC9a,H10=4.2 Hz, 3JC9a,H8=1.9 Hz, 3JC9a,H6=6.1 Hz), 149.6 (C-10b, 3JC10b,H10=3.2 Hz, 4JC10b,H6=0.9 Hz), 150.3 (C-6a, 2JC6a,H6=4.0 Hz, 3JC6a,H8=1.9 Hz, 3JC6a,H10=6.9 Hz), 153.3 (C-11a), 170.5 (C-4).
15N-NMR (50 MHz, CDCl3) δ: −193.2 (N-1), −94.5 (N-2).

Experimental

Materials and Methods

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) and on a Finnigan MAT 8230 instrument (EI, 70 eV, HRMS). IR spectra were recorded on a Perkin-Elmer FTIR Spectrum 1000 spectrometer. Elemental analyses were performed at the Microanalytical Laboratory, University of Vienna. 1H- and 13C-NMR spectra were recorded on a Varian UnityPlus 300 spectrometer at 28 °C (299.95 MHz for 1H, 75.43 MHz for 13C) or on a Bruker Avance 500 spectrometer at 293 K (500.13 MHz for 1H, 125.77 MHz for 13C). The centre of the solvent signal was used as an internal standard which was related to TMS with δ = 7.26 ppm (1H in CDCl3), δ = 2.49 ppm (1H in DMSO-d6), δ = 77.0 ppm (13C in CDCl3), and δ = 39.5 ppm (13C in DMSO-d6). The digital resolutions were 0.2 Hz/data point in the 1H and 0.4 Hz/data point in the 1H-coupled 13C-NMR spectra (gated decoupling). 15N-NMR spectra were obtained on a Bruker Avance 500 instrument with a ‘directly’ detecting broadband observe probe and were referenced against external nitromethane (coaxial capillary). Systematic names were generated with ACD/Name [26] according to the IUPAC recommendations and were also checked manually to ensure correct use of nomenclature within this publication [27]. All starting materials are commercially available and were purchased from Aldrich (1, 2a, 4a, 5a), Fluorochem (8b), Frontier Scientific (6a), or Maybridge (3a, 7b), respectively. Product yields were not optimised.

o-Haloarenecarbonyl Chlorides 2b–6b: General Procedure.

A suspension of the commercially available o-haloarenecarboxylic acid 2a, 3a, 4a, 5a, or 6a (3 mmol) in toluene (10 mL), DMF (1 drop), and excess SOCl2 (2 mL) were refluxed for 3 h. The solvent and excess SOCl2 were removed under reduced pressure. Additional toluene (5 mL) was added and the solvent was removed under reduced pressure. The remaining acid chlorides of type b were used immediately, without further purification, in the next step. Commercially available acid chlorides 7b and 8b were used as purchased. Hitherto unpublished spectroscopic data of commercially available starting materials are presented below.
3,6-Dichloropyridazine-4-carboxylic acid (2a). 1H-NMR (300 MHz, DMSO-d6) δ: 8.28 (1H, s, H-5), 9.72 (1H, s, OH); 13C-NMR (75 MHz, DMSO-d6) δ: 130.1 (C-5, 1J=181.3 Hz), 134.0 (C-4, 2JC4,H5=1.0 Hz), 152.0 (C-3, 3JC3,H5=7.5 Hz), 156.2 (C-6, 2JC6,H5=1.3 Hz), 163.0 (CO, 3JCO,H5=4.8 Hz); MS m/z (%): 196 (M+, 8), 194 (M+, 54), 192 (M+, 71), 85 (57), 84 (100), 73 (47), 51 (49), 45 (59).
4-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (3a). 1H-NMR (300 MHz, DMSO-d6) δ: 2.36 (3H, s, 3-Me), 3.32* (1H, br s, OH), 3.96 (3H, s, NMe), 8.85 (1H, s, H-6) * together with trace H2O; 13C-NMR (75 MHz, DMSO-d6) δ: 14.5 (3-Me, 1J=128.9 Hz), 33.6 (NMe, 1J=140.9 Hz), 112.6 (C-3a), 118.5 (C-5, 2JC5,H6=8.2 Hz), 138.7 (C-4, 3JC4,H6=9.1 Hz), 141.3 (C-3, 2JC3,3Me=7.1 Hz), 151.2 (C-6, 1J=186.2 Hz), 151.5 (C-7a, 3JC7a,NMe=2.3 Hz, 3JC7a,H6=14.9 Hz), 165.2 (CO, 3JCO,H6=2.3 Hz); MS m/z (%): 227 (M+, 33), 226 (M+ − 1, 29), 225 (M+, 100), 224 (M+ − 1, 65).
5-Chloro-2-(methylthio)pyrimidine-4-carboxylic acid (4a). 1H-NMR (300 MHz, DMSO-d6) δ: 2.51 (3H, s, SMe), 7.40—10.20 (1H, br s, OH), 8.84 (1H, s, H-6); 13C-NMR (75 MHz, DMSO-d6) δ: 14.0 (SMe, 1J=141.9 Hz), 121.5 (C-5, 2JC5,H6=3.8 Hz), 157.0 (C-4), 158.2 (C-6, 1J=191.7 Hz), 164.5 (CO, 4JCO,H6=1.6 Hz), 169.9 (C-2, 3JC2,SMe=4.7 Hz, 3JC2,H6=12.4 Hz); 15N-NMR (50 MHz, DMSO-d6) δ: −102.5 (N-3), −89.5 (N-1).
3-Chlorothieno[2,3-b]thiophene-2-carbonyl chloride (7b). 1H-NMR (300 MHz, CDCl3) δ: 7.31 (1H, d, 3JH4,H5=5.4 Hz, H-4), 7.51 (1H, d, 3JH5,H4=5.4 Hz, H-5); 13C-NMR (75 MHz, CDCl3) δ: 119.9 (C-4, 1J=175.5 Hz, 2JC4,H5=4.1 Hz), 127.5 (C-3, 3JC3,H4=1.0 Hz, 4JC3,H5=0.8 Hz), 131.0 (C-5, 1J=189.0 Hz, 2JC5,H4=7.0 Hz), 131.5 (C-2, 5JC2,H5=1.0 Hz), 144.5 (C-6a, 3JC6a,H5=7.8 Hz, 3JC6a,H4=9.2 Hz), 146.3 (C-3a, 2JC3a,H4=4.9 Hz, 3JC3a,H5=10.8 Hz), 156.8 (CO); MS m/z (%): 240 (M+, 3), 238 (M+, 14), 236 (M+, 18), 203 (42), 201 (100), 173 (18), 93 (15), 69 (18).
7-Chlorothieno[2,3-f][1,3]benzodioxole-6-carbonyl chloride (8b). 1H-NMR (300 MHz, CDCl3) δ: 6.13 (2H, s, H-2), 7.16 (1H, d, 5JH4,H8=0.5 Hz, H-4), 7.30 (1H, d, 5JH8,H4=0.5 Hz, H-8); 13C-NMR (75 MHz, CDCl3) δ: 101.2 (C-4, 1J=169.7 Hz), 102.1 (C-8, 1J=169.7 Hz), 102.5 (C-2, 1J=175.0 Hz), 127.4 (C-6), 130.0 (C-7, 3JC7,H8=3.8 Hz), 132.5 (C-7a, 3JC7a,H4=6.3 Hz), 136.9 (C-4a, 3JC4a,H8=7.4 Hz), 148.6 (C-8a, 2JC8a,H8=4.2 Hz, 3JC8a,H2=1.8 Hz, 3JC8a,H4=6.7 Hz), 151.5 (C-3a, 2JC3a,H4=3.8 Hz, 3JC3a,H2=1.7 Hz, 3JC3a,H8=7.2 Hz), 157.5 (CO); MS m/z (%): 278 (M+, 3), 276 (M+, 15), 274 (M+, 17), 241 (36), 239 (100), 211 (29), 201 (48), 69 (37).

Compounds 9, 10, 16–20: General Procedure.

Under anhydrous conditions, a solution/suspension of the corresponding o-haloarenecarbonyl chloride 2b–8b (3 mmol) in anhydrous 1,4-dioxane (3–5 mL) was added to a suspension of pyrazolone 1 (523 mg, 3 mmol) and Ca(OH)2 (445 mg, 6 mmol) in anhydrous 1,4-dioxane (3–5 mL). The reaction mixture was heated at reflux under stirring for 3 h. After cooling to room temperature, the mixture was acidified with 2 m HCl (5–7 ml), stirred for 15 min, and poured into H2O (10–15 ml). After 30 min, solid products were filtered off, washed with H2O, and recrystallised. NMR data of compounds 9 and 10 are presented in Table 1.
6-Chloro-3-methyl-1-phenylpyrazolo[4',3':5,6]pyrano[2,3-c]pyridazin-4(1H)-one (9). Off-white needles (yield 66%); Mp 209–212.5 °C (aqueous ethanol); IR (KBr) cm−1: 1678; MS m/z (%): 315 (M+ + 1, 6), 314 (M+, 36), 313 (M+ − 1, 27), 312 (M+, 100), 311 (M+ − 1, 45), 77 (37); Anal. Calcd. for C15H9ClN4O2 (312.7106): C, 57.61; H, 2.90; N, 17.92. Found: C, 57.83; H, 3.12; N, 17.93.
1,3,7-Trimethyl-9-phenyl-3H-pyrazolo[3,4-b]pyrazolo[4',3':5,6]pyrano[2,3-d]pyridin-6(9H)-one (10). Colourless needles (yield 63%); Mp 248.5–251 °C (aqueous ethanol); IR (KBr) cm−1: 1667; MS m/z (%): 346 (M+ + 1, 19%), 345 (M+, 100), 344 (M+ − 1, 46); Anal. Calcd. for C19H15N5O2 (345.3547): C, 66.08; H, 4.38; N, 20.28. Found: C, 65.83; H, 4.44; N, 20.35.
[5-Chloro-2-(methylthio)pyrimidin-4-yl](5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)methanone (16). Colourless needles (yield 59%); Mp 212–217 °C (aqueous ethanol); 1H-NMR (500 MHz, DMSO-d6) δ: 2.49 (3H, s, pyrazole 3-Me), 2.51 (3H, s, SMe), 7.00–10.00 (1H, br s, OH), 7.28 (1H, m, Ph H-4), 7.46 (2H, m, Ph H-3,5), 7.60 (2H, m, Ph H-2,6), 8.82 (1H, s, pyrimidine H-6); 13C-NMR (125 MHz, DMSO-d6) δ: 13.7 (pyrazole 3-Me, 1J=130.3 Hz), 14.0 (SMe, 1J=141.8 Hz), 102.6 (pyrazole C-4, 3JC4,3-Me=2.5 Hz), 120.7 (Ph C-2,6), 121.6 (pyrimidine C-5, 2JC5,H6=3.6 Hz), 126.1 (Ph C-4), 129.0 (Ph C-3,5), 135.8 (Ph C-1), 150.9 (pyrazole C-3, 2JC3,3-Me=6.7 Hz), 156.8 (pyrimidine C-6, 1J=190.5 Hz), 160.0 (pyrazole C-5), 163.0 (pyrimidine C-4, 3JC4,H6=3.7 Hz), 169.5 (pyrimidine C-2, 3JC2,SMe=4.7 Hz, 3JC2,H6=12.1 Hz), 182.8 (CO, 4JCO,H6=1.6 Hz); 15N-NMR (50 MHz, DMSO-d6) δ: −201.9 (pyrazole N-1), −102.0 (pyrimidine N-3), −93.2 (pyrimidine N-1); the pyrazole N-2 was not found; IR (KBr) cm−1: 1630; MS m/z (%): 362 (M+, 15), 360 (M+, 39), 326 (20), 325 (100), 201 (32), 159 (41), 91 (22), 77 (45); Anal. Calcd. for C16H13ClN4O2S (360.8180): C, 53.26; H, 3.63; N, 15.53. Found: C, 53.38; H, 3.78; N, 15.40.
(2-Bromo-3-thienyl)(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)methanone (17). Almost colourless crystals (yield 73%); Mp 131–133 °C (aqueous ethanol); 1H-NMR (300 MHz, CDCl3) δ: 2.05 (3H, s, Me), 7.04 (1H, d, 3JH4,H5=5.7 Hz, thiophene H-4), 7.31 (1H, m, Ph H-4), 7.38 (1H, d, 3JH5,H4=5.7 Hz, thiophene H-5), 7.47 (2H, m, Ph H-3,5), 7.86 (2H, m, Ph H-2,6), 8.81 (1H, s, OH); 13C-NMR (75 MHz, CDCl3) δ: 14.2 (Me, 1J=128.9 Hz), 104.7 (pyrazole C-4, 3JC4,Me=2.6 Hz), 113.0 (thiophene C-2, 3JC2,H5=7.6 Hz, 3JC2,H4=12.4 Hz), 120.9 (Ph C-2,6), 126.9 (Ph C-4), 127.1 (thiophene C-4, 1J=172.2 Hz, 2JC4,H5=4.2 Hz), 127.5 (thiophene C-5, 1J=189.0 Hz, 2JC5,H4=6.8 Hz), 129.1 (Ph C-3,5), 137.1 (Ph C-1), 139.2 (thiophene C-3, 2JC3,H4=5.4 Hz, 3JC3,H5=8.7 Hz), 148.3 (pyrazole C-3, 2JC3,Me=7.0 Hz), 160.3 (pyrazole C-5), 186.8 (CO); 15N-NMR (50 MHz, CDCl3) δ: −190.3 (N-1), −100.6 (N-2); IR (KBr) cm−1: 1619; MS m/z (%): 364 (M+, 7), 362 (M+, 7), 284 (18), 283 (100), 200 (13), 191 (16), 189 (13), 91 (17), 77 (26), 67 (24); Anal. Calcd. for C15H11BrN2O2S (363.2290): C, 49.60; H, 3.05; N, 7.71. Found: C, 49.63; H, 3.20; N, 7.69.
(4-Bromo-3-thienyl)(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)methanone (18). Almost colourless crystals (yield 65%); Mp 120–121 °C (aqueous ethanol); 1H-NMR (300 MHz, CDCl3) δ: 2.03 (3H, s, Me), 7.32 (1H, m, Ph H-4), 7.40 (1H, d, 3JH5,H2=3.3 Hz, thiophene H-5), 7.47 (2H, m, Ph H-3,5), 7.56 (1H, d, 3JH2,H5=3.3 Hz, thiophene H-2), 7.86 (2H, m, Ph H-2,6), 9.25 (1H, s, OH); 13C-NMR (75 MHz, CDCl3) δ: 14.5 (Me, 1J=128.9 Hz), 104.8 (pyrazole C-4, 3JC4,Me=2.6 Hz), 108.7 (thiophene C-4, 2JC4,H5=1.0 Hz, 3JC4,H2=11.9 Hz), 120.9 (Ph C-2,6), 125.0 (thiophene C-5, 1J=192.8 Hz, 3JC5,H2=4.3 Hz), 126.9 (Ph C-4), 127.7 (thiophene C-2, 1J=189.3 Hz, 3JC2,H5=5.7 Hz), 129.1 (Ph C-3,5), 137.0 (Ph C-1), 139.3 (thiophene C-3, 2JC3,H2=4.2 Hz, 3JC3,H5=8.0 Hz), 148.3 (pyrazole C-3, 2JC3,Me=6.9 Hz), 160.2 (pyrazole C-5), 186.6 (CO, 3JCO,H2=2.6 Hz); 15N-NMR (50 MHz, CDCl3) δ: −190.2 (N-1), −100.7 (N-2); IR (KBr) cm−1: 1602; MS m/z (%): 364 (M+, 42), 362 (M+, 41), 283 (100), 200 (74), 191 (39), 189 (33), 91 (40), 77 (36), 69 (36), 67 (35); Anal. Calcd. for C15H11BrN2O2S (363.2290): C, 49.60; H, 3.05; N, 7.71; S, 8.83. Found: C, 49.79; H, 2.88; N, 7.51; S, 8.66.
(3-Chlorothieno[2,3-b]thien-2-yl)(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)methanone (19). Yellowish crystals (yield 54%); Mp 193–197 °C (aqueous ethanol); 1H-NMR (300 MHz, DMSO-d6) δ: 2.29 (3H, s, Me), 4.32 (1H, s, OH), 7.30 (1H, m, Ph H-4), 7.32 (1H, d, 3JH4,H5=5.4 Hz, thienoth. H-4), 7.47 (2H, m, Ph H-3,5), 7.68 (2H, m, Ph H-2,6), 7.78 (1H, d, 3JH5,H4=5.4 Hz, thienoth. H-5); 13C-NMR (75 MHz, DMSO-d6) δ: 13.4 (Me, 1J=129.2), 105.2 (pyrazole C-4, 3JC4,Me=2.7 Hz), 118.0 (thienoth. C-3, 3JC3,H4=1.0 Hz, 4JC3,H5=0.9 Hz), 118.9 (thienoth. C-4, 1J=173.3 Hz, 2JC4,H5=4.8 Hz), 121.2 (Ph C-2,6), 126.1 (Ph C-4), 129.0 (Ph C-3,5), 131.9 (thienoth. C-5, 1J=189.3 Hz, 2JC5,H4=7.4 Hz), 136.9 (Ph C-1), 138.9 (thienoth. C-6a, 3JC6a,H5=8.0 Hz, 3JC6a,H4=9.1 Hz), 139.2 (thienoth. C-2, 5JC2,H5=0.8 Hz), 144.3 (thienoth. C-3a, 2JC3a,H4=5.1 Hz, 3JC3a,H5=10.6 Hz), 149.6* (pyrazole C-3), 156.4* (pyrazole C-5), 179.7 (CO). * broad signal; MS m/z (%): 376 (M+, 2), 374 (M+, 7), 339 (38), 218 (21), 201 (36), 200 (100), 91 (33); Anal. Calcd. for C17H11ClN2O2S2 (374.8644): C, 54.47; H, 2.96; N, 7.47. Found: C, 54.24; H, 3.04; N, 7.45.
(7-Chlorothieno[2,3-f][1,3]benzodioxol-6-yl)(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-methanone (20). Dark red powder (yield 93%); Mp 143–147.5 °C; 1H-NMR (300 MHz, DMSO-d6) δ: 2.28 (3H, s, Me), 5.32 (1H, s, OH), 6.17 (2H, s, tricycle H-2), 7.29 (1H, m, Ph H-4), 7.29 (1H, s, tricycle H-8), 7.47 (2H, m, Ph H-3,5), 7.62 (1H, s, tricycle H-4), 7.67 (2H, m, Ph H-2,6); 13C-NMR (75 MHz, DMSO-d6) δ: 13.5 (Me, 1J=129.3 Hz), 100.7 (tricycle C-8, 1J=168.1 Hz), 102.1 (tricycle C-4, 1J=170.6), 102.2 (tricycle C-2, 1J=176.3), 105.4 (pyrazole C-4, 3JC4,Me=2.5 Hz), 120.1 (tricycle C-7, 3JC7,H8=3.7 Hz), 121.2 (Ph C-2,6), 126.2 (Ph C-4), 129.0 (Ph C-3,5), 130.9 (tricycle C-7a, 3JC7a,H4=6.3), 132.3 (tricycle C-4a, 2JC4a,H4=1.6 Hz, 3JC4a,H8=7.7 Hz), 134.7 (tricycle C-6), 136.7 (Ph C-1), 147.8 (tricycle C-8a, 2JC8a,H8=3.8 Hz, 3JC8a,H4=6.9 Hz), 148.9 (tricycle C-3a, 2JC3a,H4=3.5 Hz, 3JC3a,H8=7.0 Hz), 149.7 (pyrazole C-3, 2JC3,Me=7.1 Hz), 156.7 (pyrazole C-5), 180.1 (CO); MS m/z (%): 414 (M+, 3), 412 (M+, 7), 378 (22), 377 (100), 256 (28), 212 (53), 211 (26), 200 (67), 91 (31); Anal. Calcd. for C20H13ClN2O4S (412.8462) · 0.1 H2O: C, 57.68; H, 3.24; N, 6.73. Found: C, 57.61; H, 3.38; N, 6.53.

Cyclisation of 4-Aroylpyrazol-5-ols 16–20 into Compounds 11–15; General Procedure.

Under anhydrous conditions, the corresponding 4-aroylpyrazol-5-ol 16–20 (1 mmol) was dissolved/suspended in anhydrous DMF (5 mL) and added to a suspension of NaH (60% in mineral oil; 1 mmol) in anhydrous DMF (5 mL). The reaction mixture was heated at reflux overnight and the solvent was then removed under reduced pressure. H2O (5 mL) was added to the residue and stirring was continued for 1 h further. The precipitate formed was filtered off, washed with H2O and petroleum ether and recrystallised. NMR data of compounds 11–15 are presented in Table 1.
3-Methyl-6-(methylthio)-1-phenylpyrazolo[4',3':5,6]pyrano[3,2-d]pyrimidin-4(1H)-one (11). Colour-less needles (yield 67%); Mp 242.5–244.5 °C (aqueous ethanol); IR (KBr) cm−1: 1672; MS m/z (%): 325 (M+ + 1, 18), 324 (M+, 100), 77 (22); Anal. Calcd. for C16H12N4O2S (324.3571): C, 59.25; H, 3.73; N, 17.27. Found: C, 59.29; H, 3.86; N, 17.06.
3-Methyl-1-phenylthieno[3',2':5,6]pyrano[2,3-c]pyrazol-4(1H)-one (12). Colourless needles (yield 92%); Mp 176–179 °C (aqueous ethanol); IR (KBr) cm−1: 1642; MS m/z (%): 283 (M+ + 1, 22), 282 (M+, 100), 281 (M+ − 1, 58), 77 (28); Anal. Calcd. for C15H10N2O2S (282.3171): C, 63.81; H, 3.57; N, 9.92. Found: C, 63.65; H, 3.79; N, 9.74.
3-Methyl-1-phenylthieno[3',4':5,6]pyrano[2,3-c]pyrazol-4(1H)-one (13). Beige powder (yield ≤ 5%); Mp 138–145 °C; MS m/z (%): 283 (M+ + 1, 24), 282 (M+, 100), 281 (M+ − 1, 79), 77 (27); HRMS m/z: 282.0456 (Calcd for C15H10N2O2S: 282.0463).
3-Methyl-1-phenylthieno[3'',2'':4',5']thieno[2',3':5,6]pyrano[2,3-c]pyrazol-4(1H)-one (14). Slightly yellowish needles (yield 90%); Mp 239–243 °C; IR (KBr) cm−1: 1646; MS m/z (%): 339 (M+ + 1, 21), 338 (M+, 100), 337 (M+ − 1, 45), 77 (18); Anal. Calcd. for C17H10N2O2S2 (338.4035): C, 60.34; H, 2.98; N, 8.28. Found: C, 60.15; H, 3.27; N, 8.28.
3-Methyl-1-phenyl[1,3]dioxolo[5',6'][1]benzothieno[2',3':5,6]pyrano[2,3-c]pyrazol-4(1H)-one (15). Almost colourless needles (yield 80%); Mp 324–327 °C (toluene); IR (KBr) cm−1: 1653; MS m/z (%): 377 (M+ + 1, 35), 376 (M+, 100), 375 (M+ − 1, 38), 91 (22), 77 (27); Anal. Calcd. for C20H12N2O4S (376.3853): C, 63.82; H, 3.21; N, 7.44. Found: C, 63.59; H, 3.42; N, 7.33.

Acknowledgements

We are grateful to Dr. Csaba Szántay Jr. for providing a pulse sequence for the 13C{1H} NOE-difference experiments and to Dr. L. Jirovetz for recording the mass spectra.

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Eller, G.; Holzer, W. A Convenient Approach to Heterocyclic Building Blocks: Synthesis of Novel Ring Systems Containing a [5,6]Pyrano[2,3-c]pyrazol-4(1H)-one Moiety. Molecules 2007, 12, 60-73. https://doi.org/10.3390/12010060

AMA Style

Eller G, Holzer W. A Convenient Approach to Heterocyclic Building Blocks: Synthesis of Novel Ring Systems Containing a [5,6]Pyrano[2,3-c]pyrazol-4(1H)-one Moiety. Molecules. 2007; 12(1):60-73. https://doi.org/10.3390/12010060

Chicago/Turabian Style

Eller, Gernot, and Wolfgang Holzer. 2007. "A Convenient Approach to Heterocyclic Building Blocks: Synthesis of Novel Ring Systems Containing a [5,6]Pyrano[2,3-c]pyrazol-4(1H)-one Moiety" Molecules 12, no. 1: 60-73. https://doi.org/10.3390/12010060

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