Allyl Syringate

Abstract

Syringic acid (1) is a naturally occurring compound with diverse biological activities. Structural modification of syringic acid often enhances its utility; however, the spectroscopic data for several derivatives remain unreported, and the procedures to obtain them can be synthetically challenging. In this study, we report the allylation of syringic acid (1) to afford a novel derivative, allyl syringate (1c). The structure of this compound was confirmed by IR, NMR, and MS spectroscopy and compared with those of closely related derivatives (1a and 1b). These findings provide a useful foundation for further studies on the allylation of syringic acid and related phenolic acid derivatives.

1. Introduction

Syringic acid (1), or 4-hydroxy-3,5-dimethoxybenzoic acid (Figure 1), is a naturally occurring phenolic compound present in a variety of edible plants and fruits [1,2]. It exhibits diverse biological activities, which are attributed to key functional groups—namely hydroxyl (OH), methoxy (OMe), and carboxylic acid (COOH)—attached to the aromatic ring [3]. Numerous studies have shown that derivatization of syringic acid and its analogues often yields compounds with enhanced biological activity, thereby facilitating broader investigation of their pharmacological properties [2,4,5,6,7]. However, access to such derivatives is often restricted by the synthetic challenges involved, which remain a major obstacle in the development of new bioactive molecules [8,9,10,11].

Allylated compounds, which are derivatives formed by introducing an allyl group into a molecule, have recently emerged as a major focus of scientific research owing to their versatility in organic synthesis and potential for diverse applications [12,13,14,15,16,17,18,19]. Their distinctive reactivity—particularly their capacity to undergo various allylic alkylation reactions—renders them valuable building blocks for the construction of complex molecules, including natural products and pharmaceuticals.

In general, allyl groups can be introduced into organic molecules through various strategies, including allylic substitution reactions, allylation with organometallic reagents, and C–H activation [15,20,21,22,23]. These approaches exploit the unique reactivity of the allyl moiety, enabling diverse transformations and the construction of complex molecular architectures. Although numerous methods for the allylation of organic compounds have been developed, several limitations remain in achieving efficient and highly selective reactions. Common challenges include restricted substrate scope, difficulties in controlling stereochemistry, and practical constraints in large-scale applications [24,25]. Another key limitation in chemical synthesis, particularly in certain countries, is the limited availability of specific reagents [11,26,27]. This can hinder the development of new molecules and the evaluation of their properties, ultimately slowing research and innovation across multiple fields. Reactions involving complex starting materials that contain multiple functional groups further increase the likelihood of undesired side reactions [28,29]. Selective modification of a single functional group can be challenging and minimizing byproduct formation remains a critical objective. Additionally, some allylation protocols rely on toxic reagents or harsh conditions, raising environmental concerns and restricting their broader applicability [30,31,32]. Thus, reducing reagent toxicity and employing milder reaction conditions are essential principles in advancing sustainable synthetic methodologies [33].

In the allylation of syringic acid (1), two allylated derivatives (1a–1b) have previously been prepared in reasonable yields using conventional procedures [34,35,36,37]. However, allyl syringate (1c) has not yet been reported (Scheme 1). Herein, we describe the O-allylation of syringic acid (1) using a practical and convenient method. Because allyl alcohol is not readily available in Thailand, allyl bromide—a commonly accessible reagent—was employed as the allylating agent. The O-benzoate group was successfully allylated, affording the novel derivative, allyl syringate (1c), in high yield. The structure of this compound was confirmed by spectroscopic characterization and comparison with the known derivatives (1a–1b). These findings provide useful information for future studies on the allylation of syringic acid (1) and structurally related phenolic acid derivatives.

2. Results and Discussion

2.1. The Synthesis of Allyl Syringate (1c) and Related Derivatives (1a–1b)

Syringic acid (1) contains two reactive hydroxyl groups; therefore, three allylated products can potentially be obtained: allyl syringate 4-allyl ether (1a), syringic acid 4-allyl ether (1b), and allyl syringate (1c), as mentioned earlier (Scheme 1). Our work focused on the synthesis of allyl syringate (1c) using a commonly reported base-promoted allylation procedure [38]. Allyl bromide was chosen as the allylating agent because it is commercially available and compatible with mild base conditions, although it is not considered a “green” reagent for ideal synthesis. A mixture of syringic acid (1) (1 equiv.), potassium carbonate (1 equiv.), and allyl bromide (1 equiv.) in anhydrous DMF was stirred at room temperature. After stirring the reaction for 24 h, monitored the progress of the reaction by TLC, and then purification by column chromatography, allyl syringate (1c) was afforded in 97% yield (Scheme 2).

As mentioned above, O-allylation of syringic acid (1) can afford three possible derivatives (1a–1c). To enable their unambiguous differentiation, all three compounds were synthesized, and their distinct spectroscopic characteristics were obtained. Allyl syringate 4-allyl ether (1a) was successfully prepared in excellent yield by a slight modification of a previously reported procedure [37]. Specifically, a mixture of syringic acid (1, 1 equiv.), cesium carbonate (Cs₂CO₃, 3 equiv.), and allyl bromide (4 equiv.) in anhydrous DMF was stirred at room temperature for 16 h. Subsequent purification by column chromatography afforded compound 1a in 98% yield (Scheme 3).

In the case of syringic acid 4-allyl ether (1b), the compound was obtained in high yield by a slight modification of a previously reported two-step procedure [37,39]. The one-pot sequence consisted of double allylation followed by hydrolysis of the allyl ester. Thus, a mixture of syringic acid (1, 1 equiv.), cesium carbonate (Cs₂CO₃, 3 equiv.), and allyl bromide (4 equiv.) in anhydrous DMF was stirred at room temperature for 16 h to afford crude allyl syringate 4-allyl ether (1a). Subsequent hydrolysis of the allyl ester group at 60 °C in a 1,4-dioxane/water (8:2) mixture furnished crude 1b. Purification by column chromatography gave syringic acid 4-allyl ether (1b) in 97% yield (Scheme 4).

2.2. Characterization of the Allylated Compounds (1a–1c)

In this study, the structure of the novel compound allyl syringate (1c) was confirmed and characterized using spectroscopic techniques, including IR, NMR, and MS, and the results were compared with those of the related derivatives (1a–1b) [34,35,36,37]. In the IR spectrum (see Supporting Information), allyl syringate (1c) exhibited a broad absorption band at 3408 cm⁻¹, corresponding to the O–H stretching of the phenolic group, and a strong peak at 1707 cm⁻¹, attributed to the C=O stretching of the ester. For syringic acid 4-allyl ether (1b), similar peaks were observed, together with an additional broad absorption band in the range of 3250–2750 cm⁻¹, corresponding to the O–H stretching of the carboxyl group, and a strong peak at 1682 cm⁻¹, assigned to the C=O stretching of the carboxylic acid group. In contrast, allyl syringate 4-allyl ether (1a) showed no absorption attributable to O–H stretching. Its major characteristic peak was the ester C=O stretching band, appearing at 1715 cm⁻¹.

In the ¹H and ¹³C NMR spectra, allyl syringate (1c) exhibited signals in both the aromatic region and the methoxy (OMe) substituents comparable to those observed for compounds 1a and 1b (Figure 2). In the ¹³C NMR spectra, compounds 1a and 1c, both containing an ester functional group, showed characteristic carbonyl signals at 165.9 and 166.0 ppm, respectively, whereas compound 1b, bearing a carboxylic acid group, displayed its carbonyl signal further downfield at 171.4 ppm. A comparison of the ¹H NMR spectra of 1b and 1c revealed a distinct difference in the chemical shift of the allylic methylene group: in 1b, the signal appeared at 4.62 ppm, while in 1c the corresponding allylic ether methylene signal was less shielded, appearing at 4.81 ppm (Figure 2B,C). For allyl syringate 4-allyl ether (1a), which contains both an allyl ester and an allyl ether functionality, the ¹H NMR spectrum displayed a combination of the characteristic signals of 1b and 1c (Figure 2A). Specifically, the methylene protons of the allyl groups in 1c resonated at 4.58 and 4.81 ppm, respectively.

In the mass spectrometry (MS) analysis (see Supporting Information), all three compounds (1a–1c) exhibited molecular ion peaks in good agreement with their calculated molecular weights, thereby supporting the proposed molecular structures

3. Materials and Methods

3.1. Chemicals and Instruments

Syringic acid (1) and anhydrous dimethyl formamide were purchased from Sigma-Aldrich (St. Louis, MO, USA). Allyl bromide was obtained from and Tokyo Chemical Industry (TCI, Tokyo, Japan). Melting points were determined using a Gallenkamp melting point apparatus (Loughborough, UK), and infrared (IR) spectra were recorded on a PerkinElmer 8900 spectrometer (Shelton, CT, USA) at the Department of Chemistry, School of Science, KMITL. ¹H and ¹³C NMR spectra were acquired on a JEOL JNM-ECZ-500R/S1 (500 MHz) spectrometer (Tokyo, Japan) at the Scientific Instruments Centre, School of Science, KMITL, with residual protonated chloroform (CDCl₃, δ 7.26 ppm for ¹H NMR and δ 77.00 ppm for ¹³C NMR) as internal standards. High-resolution mass spectra (HRMS) were measured using an Agilent 1260 Infinity Series instrument (Waldbronn, Germany) at the Faculty of Science, Naresuan University.

3.2. Synthesis of 4-(Allyloxy)-3,5-dimethoxybenzoate or Allyl Syringate 4-Allyl Ether (1a)

In a Schlenk tube, syringic acid (1) (59.5 mg, 0.30 mmol), allyl bromide (145.2 mg, 1.20 mmol), and cesium carbonate (293.2 mg, 0.90 mmol) were combined, and anhydrous dimethylformamide (3 mL) was added. The reaction mixture was stirred at room temperature for 16 h. Upon completion, water (30 mL) was added, and the mixture was extracted with dichloromethane (3 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the crude product was purified by flash column chromatography to afford the corresponding pure product as a colorless oil (98%). R_f = 0.83 (30% EtOAc/hexane); IR (film) 2940, 1715 (C=O), 1589, 1499, 1460, 1414, 1331, 1213, 1182, 1124, 986, 928 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.31 (2H, s, ArH), 6.12–5.98 (2H, m, OCH₂CH=CH₂), 5.40 (1H, d, J = 13.8 Hz, COOCH₂CH=CH₂), 5.32–5.27 (2H, m, OCH₂CH=CH₂), 5.18 (1H, d, J = 8.3 Hz, PhOCH₂CH=CH₂), 4.81 (2H, d, J = 4.4 Hz, COOCH₂CH=CH₂), 4.58 (2H, d, J = 4.9 Hz, PhOCH₂CH=CH₂), 3.89 (6H, s, 2 × OCH₃). ¹³C NMR (125.8 MHz, CDCl₃) δ 165.9, 153.1, 140.8, 134.0, 132.2, 125.1, 118.3, 118.2, 106.7, 74.1, 65.7, 56.2 (2 × CH₃). HRMS (ESI) Exact mass calcd for C₁₅H₁₉O₅ [M + H]⁺: 279.1233, found 279.1232. The obtained spectroscopic data were consistent with reported literature values, further confirming the proposed structure [35,36].

3.3. Synthesis of 4-(Allyloxy)-3,5-dimethoxybenzoic Acid or Syringic Acid 4-Allyl Ether (1b)

In a Schlenk tube, syringic acid (1) (59.5 mg, 0.30 mmol), allyl bromide (145.2 mg, 1.20 mmol), and cesium carbonate (293.2 mg, 0.90 mmol) were combined, and anhydrous dimethylformamide (3 mL) was added. The reaction mixture was stirred at room temperature for 16 h. After complete conversion of syringic acid (1) to compound 1a, as confirmed by TLC, sodium hydroxide (24 mg, 0.60 mmol), 1,4-dioxane (0.8 mL), and water (0.2 mL) were added, and the mixture was refluxed at 60 °C for 30 min. Upon completion, the pH was adjusted to neutral with 1 N HCl, water (30 mL) was added, and the mixture was extracted with dichloromethane (3 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the crude product was purified by flash column chromatography to afford the pure product as a white solid (97%). m.p. 109–110 °C; R_f = 0.23 (30% EtOAc/hexane); IR (film) 3250–2750 (br, OH), 2941, 1682 (C=O), 1587, 1462, 1454, 1416, 1333, 1229, 1128, 984, 768 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.37 (2H, s, ArH), 6.09 (1H, ddt, J = 13.2, 8.3, 4.9 Hz, OCH₂CH=CH₂), 5.32 (1H, d, J = 13.8 Hz, OCH₂CH=CH₂), 5.20 (1H, d, J = 8.3 Hz, OCH₂CH=CH₂), 4.62 (2H, d, J = 4.9 Hz, OCH₂CH=CH₂), 3.91 (6H, s, 2 × OCH₃). ¹³C NMR (125.8 MHz, CDCl₃) δ 171.4, 153.2, 141.6, 134.0, 124.1, 118.3, 107.4, 56.2 (2 × CH₃). Exact mass calcd for C₁₂H₁₅O₅ [M + H]⁺: 239.0920, found 239.0922. The obtained spectroscopic data were consistent with reported literature values, further confirming the proposed structure [37].

3.4. Synthesis of Allyl Syringate (1c)

In a Schlenk tube, syringic acid (1) (59.5 mg, 0.30 mmol), allyl bromide (36.3 mg, 0.30 mmol), and potassium carbonate (41.5 mg, 0.30 mmol) were combined, and anhydrous dimethylformamide (3 mL) was added. The reaction mixture was stirred at room temperature for 24 h. Upon completion, water (30 mL) was added, and the mixture was extracted with dichloromethane (3 × 15 mL). The combined organic layers were concentrated under reduced pressure, and the crude product was purified by flash column chromatography to afford the corresponding pure product as a colorless oil (97%). R_f = 0.51 (30% EtOAc/hexane); IR (film) 3408 (brs, OH), 2938, 1707 (C=O), 1611, 1514, 1460, 1423, 1364, 1331, 1275, 1209, 1184, 1111, 988, 764 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.34 (2H, s, ArH), 6.05 (1H, ddd, J = 17.9, 8.3, 4.5 Hz, OCH₂CH=CH₂), 5.92 (1H, brs, OH), 5.40 (1H, d, J = 13.7 Hz, OCH₂CH=CH₂), 5.29 (1H, d, J = 8.3 Hz, OCH₂CH=CH₂), 4.81 (2H, d, J = 4.5 Hz, OCH₂CH=CH₂), 3.94 (6H, s, 2 × OCH₃). ¹³C NMR (125.8 MHz, CDCl₃) δ 166.0, 146.6, 139.3, 132.4, 121.1, 118.2, 106.7, 65.6, 56.4 (2 × CH₃). HRMS (ESI) Exact mass calcd for C₁₂H₁₅O₅ [M + H]⁺: 239.0920, found 239.0919.

4. Conclusions

In this study, we report, for the first time, the O-allylation of syringic acid (1), affording the novel compound allyl syringate (1c) via a practical and convenient procedure. Since allyl alcohol is not readily available in Thailand, allyl bromide—a widely accessible reagent—was employed as the allylating agent. The spectroscopic characterization (IR, NMR, and MS) has been discussed in detail and compared with the known derivatives (1a–1b). These findings provide a solid foundation for future studies on the allylation and alkylation of syringic acid and structurally related phenolic acid analogues.