4a,7a-Dihydroxy-1-(2-hydroxyethyl)-5-methyl-2′,3′,4a,5′,6′,7a-hexahydrospiro[cyclopenta[b]pyridine-4,4′-pyran]-2,7(1H,3H)-dione

Abstract

An environment-friendly photochemical approach to the synthesis of 4a,7a-dihydroxy-1-(2-hydroxyethyl)-5-methyl-2′,3′,4a,5′,6′,7a-hexahydrospiro[cyclopenta[b]pyridine-4,4′-pyran]-2,7(1H,3H)-dione from 2-(4-(3-hydroxy-6-methyl-4-oxo-4H-pyran-2-yl)tetrahydro-2H-pyran-4-yl)-N-(2-hydroxyethyl)acetamide was elaborated. The suggested method is based on the ESIPT-promoted contraction of 3-hydroxypyran-4-one fragment followed by intramolecular cyclization of generated in situ α-hydroxy-1,2-diketone intermediate. The distinctive feature of the presented protocol is the employment of water as a solvent for the considered photoreaction. The structure of the obtained photoproduct was confirmed by ¹H, ¹³C-NMR, IR spectroscopy and high-resolution mass spectrometry.

1. Introduction

Photochemical reactions are an important area of organic chemistry due to their diverse applications in science and technology [1,2,3,4,5,6,7]. Numerous examples of UV-induced processes make it possible to synthesize complex, highly functional products starting from readily available materials. For example, the use of UV irradiation in total synthesis allows one to significantly shorten the preparation of natural products. It should be mentioned that the UV light can be considered as an eco-friendly traceless reagent and its use in synthetic methods is of great interest in terms of green chemistry [8,9]. From this point of view, the use of solvents that do not pollute the environment is preferable for photochemical reactions. Thus, the carrying out of phototransformations in the aqueous media is ideal within the framework of the green chemistry methodology, due to the absence of toxic reagents and solvents [10]. Therefore, the creation of photochemical synthetic protocols utilizing water as a solvent is an actual task.

2. Results

Previously, we have elaborated on the convenient method for the preparation of substituted tetrahydro-1H-cyclopenta[b]pyridine-2,7-diones based on the UV-promoted reaction of allomaltol derivatives containing the amide group [11]. Wherein, the relatively toxic acetonitrile was used as a solvent for the considered process, due to the good solubility of the starting compounds in this media. We assumed that, for a certain set of substituents in the starting allomaltol derivatives, the solubility in water can be achieved, which will allow us to carry out the proposed photoreaction under environment-friendly conditions. Continuing our research towards the development of photochemical synthetic methods [11,12,13,14,15,16,17,18,19,20], herein, we suggested a highly efficient UV-induced approach for the preparation of 4a,7a-dihydroxy-1-(2-hydroxyethyl)-5-methyl-2′,3′,4a,5′,6′,7a-hexahydrospiro[cyclopenta[b]pyridine-4,4′-pyran]-2,7(1H,3H)-dione 1 in aqueous media (Scheme 1). Target product 1 was obtained under UV irradiation with a wavelength of 312 nm of amide 2 in water, in an inert atmosphere at room temperature for 24 h. After the completion of the reaction, spiro[cyclopenta[b]pyridine-4,4′-pyran]-2,7(1H,3H)-dione 1 precipitated from the reaction mixture and separated by the usual filtration. The undoubted advantage of the presented method is the high yield of photoproduct 1 (81%) and the absence of additional purification. The structure of the obtained photoproduct was confirmed by ¹H, ¹³C-NMR, IR spectroscopy and high-resolution mass spectrometry (See Supplementary Materials).

The plausible mechanism of the considered photoprocess is depicted in Scheme 2. At first, based on the literature data, we suppose the excited state intramolecular proton transfer (ESIPT) in the pyranone fragment [21,22,23]. Under the UV light, the starting compound 2, via rapid proton transfer in the excited state A*, transforms into the photoisomer B*. Next, the relaxation of B* leads to zwitterion C, followed by the transformation of the unstable compound C to bicyclic oxirane D and opening to α-hydroxy-1,2-diketone E. Finally, intramolecular cyclization of the amide group in the side chain and carbonyl moiety of cyclopentene-1,2-dione fragment results in the target 4a,7a-dihydroxy-1-(2-hydroxyethyl)-5-methyl-2′,3′,4a,5′,6′,7a-hexahydrospiro[cyclopenta[b]pyridine-4,4′-pyran]-2,7(1H,3H)-dione 1.

3. Materials and Methods

All starting chemicals and solvents were commercially available and were used as received. Compound 2 was prepared according to a procedure described previously [11]. The NMR spectra were recorded with the Bruker DRX 300 (300 MHz) spectrometer (Billerica, MA, USA) in DMSO-d₆. Chemical shifts (ppm) were given relative to solvent signals (DMSO-d₆: 2.50 ppm (¹H NMR) and 39.52 ppm (¹³C NMR)). The high-resolution mass spectrum (HRMS) was obtained on a Bruker micrOTOF II instrument (Bruker Daltonik Gmbh, Bremen, Germany) using electrospray ionization (ESI). The melting point was determined on a Kofler hot stage (Dresden, Germany). IR spectrum was recorded on a Bruker ALPHA (Santa Barbara, CA, USA) spectrophotometer in a KBr pellet.

UV irradiation was carried out with a Vilber Lourmat VL-6.LM lamp (Marne La Vallée, France) (spectral distribution 275–370 nm with maximum intensity at 312 nm, intensity 8 mW/cm²). A photochemical reaction was performed in common borosilicate glassware at room temperature in an inert atmosphere. The distance from the light source to the irradiation vessel was 4 cm.

4. Conclusions

In summary, an eco-friendly photochemical method for the synthesis of 4a,7a-dihydroxy-1-(2-hydroxyethyl)-5-methyl-2′,3′,4a,5′,6′,7a-hexahydrospiro[cyclopenta[b]pyridine-4,4′-pyran]-2,7(1H,3H)-dione starting from 2-(4-(3-hydroxy-6-methyl-4-oxo-4H-pyran-2-yl)tetrahydro-2H-pyran-4-yl)-N-(2-hydroxyethyl)acetamide was developed. The considered approach includes ESIPT-induced contraction of allomaltol core followed by intramolecular trapping of labile α-hydroxy-1,2-diketone intermediate. The undoubted advantage of the described method is the application of water as a solvent. The structure of the synthesized spiro[cyclopenta[b]pyridine-4,4′-pyran]-2,7(1H,3H)-dione was proven by ¹H, ¹³C-NMR, IR spectroscopy and high-resolution mass spectrometry.

Experimental Procedure for the Synthesis of 4a,7a-Dihydroxy-1-(2-hydroxyethyl)-5-methyl-2′,3′,4a,5′,6′,7a-hexahydrospiro[cyclopenta[b]pyridine-4,4′-pyran]-2,7(1H,3H)-dione 1

A solution of compound 2 (1 mmol) in 20 mL of H₂O was irradiated with a Vilber Lourmat VL-6.LM lamp (312 nm, 6 W) for 24 h in common laboratory glassware at room temperature in inert atmosphere. The resulting product was filtered off and washed with H₂O (3 × 5 mL). White powder; yield 81% (0.25 g); mp 174–176°. ¹H NMR (300 MHz, DMSO-d₆) δ 6.25 (s, 1H), 6.15–5.65 (m, 2H), 3.73–3.58 (m, 3H), 3.55–3.44 (m, 3H), 3.41–3.34 (m, 2H), 2.63 (s, 2H), 2.15 (s, 3H), 1.80 (t, J = 11.8 Hz, 1H), 1.54 (d, J = 13.9 Hz, 1H), 1.37 (t, J = 13.3 Hz, 1H), 0.94 (d, J = 13.5 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ 198.74, 174.29, 168.87, 130.39, 87.09, 82.83, 62.60, 61.98, 58.37, 43.81, 37.86, 33.74, 31.01, 30.47, 17.47. IR spectrum (KBr), ν, cm⁻¹: 3443, 3233, 3064, 3016, 2958, 2899, 2864, 2766, 2689, 2484, 2297, 1955, 1717, 1626, 1468, 1422, 1407, 1347, 1322, 1292, 1257, 1195, 1154, 1133, 1100, 1072, 1021, 974. HRMS (ESI-TOF) m/z: [M + H]⁺ Calcld for C₁₅H₂₁NO₆ + H⁺: 312.1442; Found: 312.1443.

Author Contributions

A.N.K.—conceptualization, synthesis, spectroscopic analysis and writing of the manuscript. B.V.L.—conceptualization, synthesis, spectroscopic analysis and writing of the manuscript. V.G.M.—conceptualization, synthesis, spectroscopic analysis and writing of the manuscript. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data for the compounds presented in this study are available in the Supplementary Materials of this article.

Conflicts of Interest

The authors declare no conflict of interest.

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Schemes

Scheme 1. Photochemical synthesis of compound 1.

Scheme 2. Proposed reaction mechanism.

Supplementary Materials

The following supporting information are available online: copies of ¹H, ¹³C-NMR, mass and IR spectra for compound 1. Figure S1: ¹H NMR spectrum (300 MHz) of compound 1 in DMSO-d₆; Figure S2: ¹³C {¹H} NMR spectrum (75 MHz) of compound 1 in DMSO-d₆; Figure S3: HRMS for compound 1; Figure S4: IR spectrum for compound 1.

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