(RS)-6,6,7′,7′-Tetramethyl-2-sulfanylidene-5,6,6′,7′-tetrahydro-2H,2′H,4H,4′H,5′H-spiro[thiopyran-3,3′-thiopyrano [2,3-b]thiopyran]-4,5′-dione

Abstract

The reaction of aliphatic aldehydes with the tautomers 6,6-dimethyl-4-hydroxy-2H-thiopyrane-2-thione and 6,6-dimethyl-2-mercapto-4H-thiopyrane-4-one is reported to yield spiro compounds. However, the spiro compound of the reaction with formaldehyde is postulated, but has not been isolated to date. Due to a change in reaction conditions, we managed to isolate (RS)-6,6,7′,7′-Tetramethyl-2-sulfanylidene-5,6,6′,7′-tetrahydro-2H,2′H,4H,4′H,5′H-spiro[thiopyran-3,3′-thiopyrano [2,3-b]thiopyran]-4,5′-dione for the first time. The structure was proven with the help of a single X-ray crystal analysis. Furthermore, the new compound was fully characterized using one- and two- dimensional NMR techniques such as ¹H, ¹³C, DEPT, COSY, HSQC and HMBC spectra, as well as IR and HRMS measurements.

1. Introduction

Schweiger et al. reported the synthesis of spiro compounds from aliphatic aldehydes and of the tautomers 6,6-dimethyl-4-hydroxy-2H-thiopyrane-2-thione and 6,6-dimethyl-2-mercapto-4H-thiopyrane-4-one [1]. The synthesis of two 2′,4′-dialkyl-6,6,7′,7′-Tetramethyl-2-sulfanylidene-5,6,6′,7′-tetrahydro-2H,2′H,4H,4′H,5′H-spiro[thiopyran-3,3′-thiopyrano [2,3-b]thiopyran]-4,5′-diones is described as having two asymmetric centres in position 2′ and 4′. The aim of this work was to investigate if it is possible to prepare a derivative which is not substituted in these positions to avoid diastereomeric mixtures and pave the way for derivatizations of an interesting spiro skeleton which has scarcely been described until now.

2. Results

The reported synthesis [1], shown in Scheme 1, was started from the tautomers 1 and 2 and was carried out in ethanol with the molar ratio of aldehyde/1 and 2 = 1:1, reflux, 4 h or in chloroform with the molar ratio of aldehyde/1 and 2 = 1.5:1, reflux, 5 h. In both cases, mainly compounds 3a–3c were formed and isolated using crystallization. From the filtrates, compounds 4b and 4c were isolated using CC over silica gel. Compounds 4b and 4c were isolated as the main products when the reaction was carried out in benzene with the molar ratio of aldehyde/1 and 2 = 1:1 and under 5 h reflux on a water separator or when 1 and 2 were treated with a large excess of aldehyde for 6 h under reflux [1]. In any of these cases, it was not possible to isolate 4a since the separation using CC was hindered by an unknown impurity.

We repeated the procedure with ethanol and prolonged the reaction time for one hour, but not a trace of the spiro compound 4a was found in the reaction mixture. When we used a 37% formaldehyde solution instead of paraformaldehyde and added a molar amount of ammonium chloride to the reaction mixture, a precipitate was formed after 10 min. The latter was sucked off, dried, dissolved in DMSO and heated for 20 min to 175 °C. From this reaction mixture, we were able to isolate 4a.

The structure of 4a was confirmed with the aid of a single X-ray crystal analysis (see Figure 1) and further characterization was performed using one- and two-dimensional NMR techniques, infrared spectra and high-resolution mass spectra.

Following long-range couplings in HMBC spectra supporting the structure, the thiopyran-thion carbon C-2 at 240 ppm showed couplings to H-2′ and H-4′, the oxo function C-4 at 202 ppm to H-2′ and H-4′, the oxo function C-5′ at 190 ppm to H-6′, the quaternary C-8a’ at 148 ppm to H-2′ and H-4′, the quaternary C-4a’ at 123 ppm to H-2′ and H-4′ and the spiro carbon C-3 at 66 ppm to H-2′, H-4′ and H-5. The signals for the four methyl groups were assigned using the long-range coupling of their protons to C-6 and C-7′, respectively. The position of C-6 was given by the long-range coupling to protons in position 5 and they showed, as mentioned above, interactions with spiro carbon C-3. In addition, w-couplings were observed between H-2′ and H-4′, as shown in Figure 2.

In IR spectra, typical peaks for the ketone in position 4 at 1715 cm⁻¹ and at 1630 cm⁻¹ for the double bond were found. Additionally, a peak for the thiopyran-thione [2] at 1538 cm⁻¹ was observed. Two methods of high-resolution mass spectra (DIP-EI and HESI) confirmed the molecular mass. Homogeneity was proven by a chromatographic method. All NMR and crystal data as well as HPLC data are reported in the supplementary material.

3. Materials and Methods

3.1. Instrumentation and Chemicals

The tautomeric mixture of 1 and 2 was prepared as reported [3]. Solvents were used without further purification. Melting points were obtained on the digital melting point apparatus Cole-Parmer MP250 (Alessandria, Italy). IR spectra: Bruker Alpha Platinum ATR FT-IR spectrometer (Faellanden, Switzerland). Frequencies are reported in cm⁻¹. Peaks are described as strong (s), medium (m) and weak (w). NMR spectra: Nuclear magnetic resonance spectrometer Bruker Avance 400 (Faellanden, Switzerland), (300 K) 5 mm tubes; spectra were acquired in DMSO. Chemical shifts were recorded in parts per million (ppm). The proton signal at 2.49 ppm served as internal reference as well as the central peak of the DMSO-d₆ signal at 39.7 ppm. Signal multiplicities are abbreviated as follows: s, singlet; d, doublet; dd, double–doublet. Coupling constants (J) are reported in Hertz (Hz). 1 H and 13 C resonances were assigned using 1 H, 1 H- and 1 H, 13 C-correlation spectra. 1 H and 13 C resonances are numbered as given in the formulae. HRMS: Electron ionization (EI+, 70 eV, source at 250 °C) mass spectra were acquired on a JMS-T2000GC (AccuTOFTM GC-Alpha) from JEOL Ltd. (Tokyo, Japan) equipped with a direct insertion probe (DIP), and HESI spectra were recorded on a Q Exactive Hybrid Quadrupole-Orbitrap mass spectrometer, Thermo Fisher Scientific, Austin, TX, USA (HESI, capillary voltage 3.5 kV). Thin-layer chromatography (TLC): TLC plates (Merck, Darmstadt, Germany, silica gel 60 F254 0.2 mm, 200 × 200 mm); the substance was detected in UV light at 254 nm. Purity and homogeneity of 4a was assessed by a HPLC separation method, using an Ultimate 3000 UHPLC system equipped with a photodiode array (PDA) and hyphenated to a Q Exactive Hybrid Quadrupol-Orbitrap MS (Thermo Fisher Scientific). Column: Acquity^TM, Milford, MA, USA, Premier BEH 1.7 μm, 2.1 × 100 mm column protected by Acquity^TM UPLC BEH C18 1.7 μm VanGuard^TM, Malvern, PA, USA, guard column (Waters). Mobile phase: A: H₂O + 0.1%HCOOC, B: MeCN. Gradient: 0–10 min, 10–100% B in A, 10–12 min, 100% B, 12–12.5 min, 100–10% B, 12.5–16 min, 10% B. Column temperature: 40 °C.

3.2. Synthesis of (RS)-6,6,7′,7′-Tetramethyl-2-sulfanylidene-5,6,6′,7′-tetrahydro-2H,2′H,4H,4′H,5′H-spiro[thiopyrane-3,3′-thiopyrano [2,3-b]thiopyran]-4,5′-dione 4a

To a solution of tautomeric mixture 1 and 2 (1.74 g, 10 mmol) in ethanol (50 mL), ammonium chloride (535 mg, 10 mmol) was added as well as a solution of formaldehyde (37%, 854 mg, 10.5 mmol). The mixture was refluxed for 10 min in an oil bath (117–119 °C) and precipitation took place. It was left for crystallization at r.t. for three days. Then the mixture was stirred on an ice bath, the solid sucked off and dried over phosphorous pentoxide in a desiccator. The dry solid was suspended in DMSO (16 mL) and the mixture heated for 20 min in an oil bath at 175 °C. Demineralized water (500 mL) was added to the resulting dark red solution and the formed emulsion transferred into a separatory funnel and extracted 7 times with heptane. The combined organic phases were dried with sodium sulfate, filtered and the solvent evaporated giving a dark red resin (800 mg, 43%) which was nearly pure 4a. The resin was dissolved in the minimum amount of hot methanol and left for crystallization overnight at r.t. The red crystals were sucked off and dried to give the product 4a (287 mg, 15%) as red plates. m.p.: 165 °C; R_f (CH₂Cl₂:CH₃OH = 20:1) = 0.80; R_f (CH₂Cl₂:CH₃OH = 1:1) = 0.91; IR (ν_max) = 1715 (m), 1628 (s), 1538 (s), 1367 (w), 1338 (m), 1306 (m), 1279 (m), 1212 (s), 1163 (w), 1123 (w), 982 (s), 951 (w), 928 (w), 892 (w), 877 (w) cm⁻¹; ¹H NMR (DMSO-d₆, δ 400 MHz): 1.36 (s, 6H, 6-CH₃, 7′-CH₃), 1.38 (s, 3H, 7′-CH₃), 1.48 (s, 3H, 6-CH₃), 2.60 (d, J = 16.4 Hz, 1H, 6′-H), 2.79 (d, J = 12.0 Hz, 1H, 5-H), 2.85 (d, J = 16.5 Hz, 1H, 6′-H), 2.94 (dd, J = 17.2, 2.4 Hz, 1H, 4′-H), 3.05 (d, J = 17.1 Hz, 1H, 4′-H), 3.36 (d, J = 13.1 Hz, 1H, 2′-H), 3.80 (d, J = 11.6 Hz, 1H, 5-H), 3.83 (dd, J = 13.2, 2.4 Hz, 1H, 2′-H) ppm; ¹³C NMR (DMSO-d₆, δ, 100 MHz): 26.11 (7′-CH₃), 28.3 (7′-CH₃), 29.7 (6-CH₃), 30.3 (6-CH₃), 30.5 (C-4′), 39.4 (C-2′), 47.1 (C-7′), 47.9 (C-5), 52.0 (C-6), 52.6 (C-6′), 66.2 (C-3), 123.4 (C-4a’), 147.6 (C-8a’), 190.0 (C-5′), 201.9 (C-4), 239.7 (C-2) ppm; HRMS (DIP-EI): calcd. C₁₆H₂₀O₂S₄ [M]⁺: 372.0341; found: 372.0343; HRMS (HESI): calcd. C₁₆H₂₁O₂S₄ [M + H]⁺: 373.0419; found: 373.0410; HPLC separation confirmed 96% purity based on integration of peak areas detected by PDA.

3.3. X-Ray Structure Determination of 4a

Single red plate-shaped crystals of 4a were recrystallized from methanol. A suitable crystal with dimensions 0.11 × 0.08 × 0.03 mm³ was selected and mounted on a MiTeGen, Ithaca, NY, USA, loop on an XtaLAB Synergy, Dualflex, HyPix-Arc 100 diffractometer (Tokyo, Japan). Reflection data were collected at T = 100 K using monochromatized Cu K_α radiation (λ = 1.54184 Å). Data reduction, scaling and absorption corrections were performed using the CrysAlisPro software (1.171.43.120a) [4]. A numerical absorption correction based on gaussian integration over a multifaceted crystal model and an empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm, were performed. The absorption coefficient µ of this material is 5.030 mm⁻¹ at this wavelength and the minimum and maximum transmissions are 0.593 and 1.000.

The structure was solved with the ShelXT [5] structure solution program using the intrinsic phasing solution method and by using Olex2 [6] as the graphical interface. The model was refined with version 2019/3 of ShelXL [7] using full-matrix least-squares techniques against F². All non-hydrogen atoms were refined anisotropically. Hydrogen atom positions were calculated geometrically and refined using a riding model.

Crystal data for C₁₆H₂₀O₂S₄, M_r = 372.56, monoclinic, P2₁/n (No. 14), a = 7.60960(10) Å, b = 27.9654(4) Å, c = 8.26570(10) Å, β = 97.3050(10)°, α = γ = 90°, V = 1744.71(4) ų, T = 100.0(2) K, Z = 4, Z′ = 1, µ(Cu K_α) = 5.030 mm⁻¹, 18,900 reflections measured, 3697 unique (R_int = 0.0394) which were used in all calculations. The final wR₂ was 0.0644 (all data) and R₁ was 0.0262 (I ≥ 2σ(I)). All atoms of the complex lie on general positions. Further crystal data and refinement for 4a are presented in

Table 1. Crystal data and structure refinement for 4a.

Empirical formula	C16H20O2S4
Formula weight	372.56
Temperature/K	100.0(2)
Crystal system	monoclinic
Space group	P21/n
a/Å	7.60960(10)
b/Å	27.9654(4)
c/Å	8.26570(10)
α/°	90
β/°	97.3050(10)
γ/°	90
Volume/Å3	1744.71(4)
Z	4
ρcalc g/cm3	1.418
μ/mm−1	5.030
F(000)	784.0
Crystal size/mm3	0.11 × 0.08 × 0.03
Radiation	Cu Kα (λ = 1.54184 Å)
2Θ range for data collection/°	6.322 to 154.72
Index ranges	−9 ≤ h ≤ 9, −35 ≤ k ≤ 35, −7 ≤ l ≤ 10
Reflections collected	18,900
Independent reflections	3697 [Rint = 0.0394, Rsigma = 0.0300]
Data/restraints/parameters	3697/0/203
Goodness-of-fit on F2	1.051
Final R indexes [I ≥ 2σ (I)]	R1 = 0.0262, wR2 = 0.0628
Final R indexes [all data]	R1 = 0.0303, wR2 = 0.0644
Largest diff. peak/hole/e.Å−3	0.35/−0.20

. The final atomic parameters, as well as bond lengths and angles, were deposited at the Cambridge Crystallographic Data Centre. CCDC 2497225 contains the Supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (accessed on 22 October 2025), (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).