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Unexpected Metal-Free Dehydrogenation of a β-Ketoester to a Phenol Using a Recyclable Oxoammonium Salt

Unexpected Formation of 4-aryl-1-(Propane-2-ylidenehydrazono)-2,3-diazaspiro[5.5]undec-3-ene by the Reaction of Pyridazinethiones Derivatives with Hydrazine

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1111 Budapest, Hungary
Author to whom correspondence should be addressed.
Academic Editors: Stefano D’Errico and Annalisa Guaragna
Molbank 2021, 2021(3), M1243;
Received: 26 May 2021 / Revised: 15 June 2021 / Accepted: 15 June 2021 / Published: 2 July 2021
(This article belongs to the Special Issue Molecules from Side Reactions II)


After making a new series of spiro[cycloalkane]pyridazinones with high Fsp3 character available, the new target was to synthesize derivatives comprising nitrogen-containing heterocycles, such as triazolo or tetrazolo rings. The corresponding thioxo derivatives (1a,b) seemed to be good starting materials for the synthesis of tetrazolo derivatives. The reaction of the pyridazinethiones (1a,b) with hydrazine surprisingly resulted in Schiff bases (3a,b) deriving from the reaction of hydrazones (2a,b) with acetone.
Keywords: pyridazinethione; spiro[cycloalkane]pyridazine; hydrazine; acetone; Schiff base pyridazinethione; spiro[cycloalkane]pyridazine; hydrazine; acetone; Schiff base

1. Introduction

The molecule bank of a company might play an important role in the early phase of preclinical drug discovery. To find a hit, a high-throughput screening (HTS) campaign may be a useful tool [1]. In the design of new compounds for a molecule bank, the application of some widely used rules (Lipinski rule of five, Veber’s rule) [2,3,4] and other concepts of medicinal chemistry, such as the role of aromatic rings or bioisosteric nitrogen-containing heterocycles, are of key importance [5,6,7,8]. Lovering introduced the Fsp3 character, which usually shows a good correlation with logP and other physicochemical parameters [9,10]. With the consideration of the above aspects, a series of spiro[cycloalkane]pyridazinones with high Fsp3 character and advantageous physicochemical parameters was synthetized [11,12,13]. Starting from 2-oxaspiro[4.4]nonane-1,3-dione and 2-oxaspiro[4.5]-1,3-dione, the ketocarboxylic acids were obtained by Friedel-Crafts or Grignard reaction. The ring closure took place with hydrazine or its derivatives: methylhydrazine and phenylhydrazine. A few of the obtained dihydropyridazine derivatives were alkylated. The corresponding pyridazinonethiones (1) were prepared by the reaction of pyridazinones with phosphorus pentasulfide [14] (Scheme 1).

2. Results and Discussion

We wanted to extend this compound family with further examples, combining the spiro[cycloalkane]pyridazines with nitrogen-containing heterocycles, such as triazole or tetrazole. The hydrazone derivatives of 1a,b may be important intermediates for the synthesis of tetrazoles. To obtain these compounds, the reaction of pyridazinethiones (1a and 1b) with hydrazine in tetrahydrofuran was studied [14]. In the case of the chloro and methyl derivatives, the E and Z stereoisomers of the desired hydrazones (2a (R = CH3, yield: 59%) and 2b (R = Cl, yield:61%)) were obtained surprisingly with a small amount of a side product (3a and 3b), which is the Schiff base of the expected hydrazones with acetone (3a,b). The structures of the isolated by-products were established by detailed 1H and 13C NMR and HRMS studies. The hydrazones (2a R = CH3 and 2b R = Cl) might have been the intermediates, which reacted with the trace amount of acetone present in the glassware. Reacting the hydrazones (2a R = CH3 and 2b R = Cl) with sodium nitrite, the corresponding tetrazole derivatives (4a R = CH3 and 4b R = Cl) were obtained smoothly [14]. According to the database SciFinder, the compounds 3a and 3b (R = CH3, Cl) are new compounds, which may be valuable members of a molecule bank. Table 1 summarizes the most important physicochemical parameters of 3a,b. Interestingly the Fsp3 character of compounds 3a,b is high, but the logP and clogP values (4.6–5.2) are not advantageous enough.

3. Materials and Methods

3.1. General Information, TLC, Preparative TLC

Hydrazine hydrate [10217-52-4], tetrahydrofuran [109-99-9], dichloromethane [75-09-2], heptane [142-82-5], methanol [67-56-1] were purchased from SigmaAldrich. TLC was carried out using Kieselgel 60 F254 (Merck 1.05554.0001). The analytical samples for NMR and HRMS studies were purified by preparative TLC using Kieselgel 60 F254 (Merck 1.07748.1000) coated glass plates.

3.2. NMR Spectroscopy

NMR measurements were performed on a Varian VNMRS 400 MHz NMR spectrometer equipped with a 15N-31P{1H-19F} 5 mm OneNMR room temperature probe, a Varian VNMRS 500 MHz NMR spectrometer equipped with a 1H {13C/15N} 5 mm PFG Triple Resonance 13C Enhanced Cold Probe, a Varian VNMRS 800 MHz NMR spectrometer equipped with a 1H{13C/15N} TripleResonance13C Enhanced Salt Tolerant Cold Probe (Varian, Inc., Palo Alto, CA, USA), a Bruker Avance III HDX 500 MHz NMR spectrometer equipped with a 1H {13C/15N} 5 mm TCI CryoProbe, and a Bruker Avance III HDX 500 MHz NMR spectrometer equipped with a 1H-19F{13C/15N} 5 mm TCI CryoProbe (Bruker Corporation, Billerica, MA, USA). 1H and 13C chemical shifts are given on the delta scale as parts per million (ppm) with tetramethylsilane (TMS) (1H, 13C) or dimethylsulfoxide-d6(13C) as the internal standard (0.00 ppm and 39.4 ppm, respectively). 1H-1H, direct 1H-13C, and long-range 1H-13C scalar spin–spin connectivity were established from 2D COSY, TOCSY, HSQC, and HMBC experiments. 1H-1H spatial proximities were determined using two-dimensional NOESY or ROESY experiments. 15N Chemical shifts are referenced to nitromethane (0.0 ppm) and are obtained from 1H-15N HMBC measurements. All pulse sequences were applied by using the standard spectrometer software package. All experiments were performed at 298 K. NMR spectra were processed using VnmrJ 2.2 Revision C (Varian, Inc. Palo Alto, CA, USA), Bruker TopSpin 3.5 pl 6 (Bruker Corporation, Billerica, MA, USA), and ACD/Spectrus Processor version 2017.1.3 (Advanced Chemistry Development, Inc., Toronto, ON, Canada).

3.3. Mass Spectrometry

HRMS and MS-MS analyses were performed on a ThermoVelos Pro Orbitrap Elite (Thermo Fisher Scientific) system. The ionization method was ESI operated in positive ion mode. The protonated molecular ion peaks were fragmented by CID at a normalized collision energy of 35%. For the CID experiment, helium was used as the collision gas. The samples were dissolved in methanol. Data acquisition and analysis were accomplished with Xcalibur software version 2.0 (Thermo Fisher Scientific, Waltham, MA, USA).

3.4. General Procedure for the Preparation of 1-(Propane-2-ylidenehydrazono)-4-(p-substituted phenyl)-2,3-diazaspiro[5.5]undec-3-ene (3a,3b)

The hydrazine monohydrate (0.10 mL, 1.2 mmol) was dissolved in THF (5 mL), and then the corresponding pyridazinethione derivatives (1a,b) (0.40 mmol) were also dissolved in THF (15 mL) and added dropwise to the hydrazine solution. The reaction mixture was stirred at reflux for 12 h, and then the solvent was evaporated. The residue was dissolved in dichloromethane (20 mL) and washed with distilled water (2 × 10 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude productwas purified by preparative thin-layer chromatography (eluent: heptane:dichloromethane:methanol/5:5:1) to give by-products and hydrazone derivatives.
1-(Propan-2-ylidenehydrazono)-4-(p-tolyl)-2,3-diazaspiro[5.5]undec-3-ene (3a) Yield: 14%;Rf(heptane:dichloromethane:methanol/5:5:1) = 0.48,1H NMR (499.9 MHz; DMSO-d6) δ = 1.31–1.71 (m, 10H, cyclohexyl); 1.94 (s, 3H, H-3’); 1.97 (s, 3H, H-1’); 2.37 (s, 3H, C(4’’)-CH3); 2.72 (s, 2H, H-5); 7.22 (m, 2H, H-3”, H-5”); 7.67 (m, 2H, H-2”, H-6”); 9.75 (br s, 1H, NH-2) ppm; 13C NMR (125.7 MHz; DMSO-d6) δ = 17.52 (C-3’); 20.72 (C-4”-CH3); 20.97 (C-8, C-10); 25.51 (C-9); 27.77 (C-1’); 30.75 (C-5); 32.75 (C-7, C-11); 33.31 (C-6); 124.88 (C-2”, C-6”); 128.98 (C-3”, C-5”); 134.32 (C-1”); 134.32 (C-4”); 145.67 (C-4); 153.55 (C-1), 160.79 (C-2’) ppm; 15N NMR (40.5 MHz; DMSO-d6) δ = −333.48 (N-2’); −306.25 (N-3); −145.69 (N-2); (N-1) ppm; HRMS: M + H = 311.22313 (delta = 0.3 ppm; C19H27N4). MS-MS (CID = 35%; rel. int. %): 282(100); 267(31); 255(13); 239(24); 227(8); 212(39); 199(10); 186(3); 138(2).
4-(4-Chlorophenyl)-1-(propan-2-ylidenehydrazono)-2,3-diazaspiro[5.5]undec-3-ene (3b) Yield: 7%; 1H NMR (499.9 MHz; DMSO-d6) δ = 1.31–1.71 (m, 10H, cyclohexyl); 1.94 (s, 3H, H-3’); 1.97 (s, 3H, H-1’); 2.74 (s, 2H, H-5); 7.46 (m, 2H, H-3”, H-5”); 7.80 (m, 2H, H-2”, H-6”); 9.90 (s, 1H, NH-2) ppm; 13C NMR (125.7 MHz; DMSO-d6) δ = 17.55 (C-3’); 20.93 (C-8, C-10); 24.77 (C-1’); 25.50 (C-9); 30.68 (C-5); 32.78 (C-7, C-11); 33.20 (C-6); 126.65 (C-2”, C-6”); 128.40 (C-3”, C-5”); 133.00 (C-4”); 135.93 (C-1”); 144.31 (C-4); 153.10 (C-1), 161.10 (C-2’) ppm; 15N NMR (40.5 MHz; DMSO-d6) δ = −333.80 (N-2’); −309.88 (N-3); −267.65 (N-1’); −147.14 (N-2) ppm; HRMS: M + H = 331.16715 (delta = −3.8 ppm; C18H24N4Cl). HR-ESI-MS-MS (CID = 45%; rel. int. %): 302(100); 301(17); 287(30); 275(10); 261(12); 259(17); 247(10); 232(33).

4. Conclusions

Reacting spiro[cycloalkane]pyridazinethiones with hydrazine in tetrahydrofuran, the desired hydrazones and, surprisingly, their Schiff bases with acetone were obtained. The hydrazones might have reacted with the acetone present in the glassware. The structures of the isolated p-substituted 4-aryl-1-(propane-2-ylidenehydrazono)-2,3- diazaspiro[5.5]undec-3-enes (3a,3b) have been fully characterized by 1H, 13C, 15N NMR and HRMS.

Supplementary Materials

The following are available online: HRMS, 1H, and 13C NMR spectra of 3a,b.

Author Contributions

C.S.F. and H.B. planned the experiments. C.S.F. carried out the experimental work. H.B. managed the project and wrote the paper. G.K. was the consultant. All authors have read and agreed to the published version of the manuscript.


C.S.F. is grateful for the support of the Gedeon Richter’s Centenárium Foundation.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available within the article or supplementary material.


The authors are grateful to Áron Szigetvári for the NMR and Miklós Dékány for the HRMS studies.

Conflicts of Interest

The authors declare no conflict of interest.


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Scheme 1. Synthesis of hydrazone and tetrazolo derivatives starting from spiro[cycloalkane]pyridazinethiones.
Scheme 1. Synthesis of hydrazone and tetrazolo derivatives starting from spiro[cycloalkane]pyridazinethiones.
Molbank 2021 m1243 sch001
Table 1. The physicochemical parameters of the hydrazone derivatives.
Table 1. The physicochemical parameters of the hydrazone derivatives.
Starting MaterialR1ProductFsp3LogPClogPTPSA
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