9-(4-Hydroxybutyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione

Abstract

The title compound 9-(4-hydroxybutyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione was synthesized in 72% yield through a simple, convenient and environmentally friendly one-pot reaction between dimedone and 3,4-dihydro-2H-pyran in aqueous citric acid. Additionally, a plausible reaction mechanism for the formation of the target xanthene is proposed.

1. Introduction

Xanthenes are a very interesting class of oxygen-containing heterocycles with a large number of synthetic and naturally occurring derivatives [1,2,3] that exhibit diverse applications in the field of medicinal chemistry [4,5] and materials science [6,7]. In particular, the hexahydro-1H-xanthene-1,8(2H)-diones have shown potential as antioxidant, [8] anticancer [9,10] and leishmanicidal agents [11].

The synthesis of hexahydro-1H-xanthene-1,8(2H)-diones is commonly performed by the condensation of the appropriate aldehyde and dimedone or 1,3-cyclohexanedione under verious various conditions which include the use of alternative solvents [12,13,14,15], homogeneous [16,17], and heterogeneous [18,19,20] catalysts, and ultrasound- [21,22] or microwave-assisted [23] synthesis.

In this paper we describe the synthesis of 9-(4-hydroxybutyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione, a novel hexahydroxanthene, using an environ-mentally friendly one-pot reaction.

2. Results and Discussion

For the preparation of the target xanthene 3, one equivalent of 3,4-dihydro-2H-pyran 2 was reacted with two equivalents of dimedone 1 in 0.3 M citric acid in a closed vessel at 90 °C during 8 h (Scheme 1). After reaction completion (monitoring by thin layer chromatography) and purification by recrystallization, the desired title compound 3 was isolated in 72% yield.

The title compound was characterized by IR, ¹H-NMR, ¹³C-NMR and elemental analysis. As expected, the IR spectrum shows the OH band at 3390 cm⁻¹ and a strong absorption band at 1664 and 1643 cm^–1 for the C=O stretching vibration. The proton NMR spectrum showed the following signals: singlet at 1.10 ppm assigned to the CH₃ groups, three multiplets centered at 1.15, 1.48 and 1.55 ppm assigned to three CH₂ groups of the alkyl chain, a broad singlet at 1.60 ppm assigned to the OH proton, two doublets at 2.24 and 2.30 ppm assigned to two CH₂ groups of the xanthene core, a singlet at 2.37 ppm assigned to two CH₂ groups of the xanthene core and two triplets at 3.55 and 3.78 ppm corresponding to CH₂OH and CH groups respectively.

Scheme 1. Synthesis of 9-(4-hydroxybutyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione 3.

Scheme 1. Synthesis of 9-(4-hydroxybutyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione 3.

A plausible mechanism for the formation of compound 3 is given in Scheme 2. First, the hydrolysis in situ of the cyclic enol ether takes place yielding the cyclic hemiacetal 4 [24] which is in equilibrium with its ring-opened form 5-hydroxypentanal 5 [25]. This aldehyde 5 forms the Knoevenagel adduct 6 by the reaction of the enolic form of dimedone promoted by citric acid. Then 6 may further undergo Michael addition with another molecule of dimedone, in its enol form, to yield intermediate 7, which after an intramolecular cyclization and dehydration gives compound 3.

Scheme 2. Plausible mechanism for the formation of the new hexahydro-1H-xanthene-1,8(2H)-dione 3.

Scheme 2. Plausible mechanism for the formation of the new hexahydro-1H-xanthene-1,8(2H)-dione 3.

3. Experimental Section

3.1. General Information

Melting points, reported without correction, were measured using a Stuart SMP10 apparatus (Stuart, Staffordshire, UK). The FT-IR spectra were obtained with a Shimadzu IR prestige 21 spectrophotometer (Columbia, MD, USA). ¹H and ¹³C-NMR spectra were recorded with a Bruker AVANCE III system (Billerica, MA, USA) operating at 400 MHz, using residual (δ_H 7.26) and deuterated solvent (δ_C 77.0) peaks of CDCl₃ as reference standards. The elemental analysis was performed on a Thermo Scientific Flash 2000 CHNS/O analyzer (Waltham, MA, USA). Reagents and solvents were obtained from commercial sources and used without further purification. 0.3 M citric acid was prepared using distilled and deionized water.

3.2. Synthesis of 9-(4-Hydroxybutyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione

A mixture of dimedone 1 (80.9 mg, 0.58 mmol) and dihydro-2H-pyran 2 (26.3 μL, 0.29 mmol) in 2 mL of 0.3 M citric acid was placed in a 10 mL glass vial. The vial was sealed and stirred at 90 °C for 8 h. After cooling the mixture the product was recovered by filtration. The solid was finally purified by recrystallization from a mixture ethanol/water (1/1). The target compound 3 (72.0 mg, 72%) was recovered as white crystals, m.p: 125–127 °C. FT-IR (ATR): 3514, 3390, 2958, 2933, 1664, 1643, 1616, 1348, 1192, 1136, 1064, 1001 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 1.10 (s, 12H, 4CH₃), 1.12–1.18 (m, 2H, CH₂ alkyl), 1.46–1.51 (m, 2H, CH₂ alkyl), 1.51–1.57 (m, 2H, CH₂ alkyl), 1.60 (bs, 1H, OH), 2.24 (d, 2H, J = 16.2 Hz, CH₂ xanthene), 2.30 (d, 2H, J = 16.2 Hz, CH₂ xanthene), 2.37 (s, 4H, 2CH₂ xanthene), 3.55 (t, 2H, J = 6.5 Hz, CH₂OH), 3.78 (t, 1H, J = 4.5 Hz, CH). ¹³C-NMR (100 MHz, CDCl₃) δ(ppm): 21.5, 25.2, 27.3, 29.4, 32.0, 32.6, 33.6, 40.9, 50.9, 62.7, 114.9, 164.0, 197.2. Anal. calcd for C₂₁H₃₀O₄: C, 72.80; H, 8.73. Found: C, 72.53; H, 8.68.