1,1-Bis(4-ethylphenyl)-propan-1,2-diol

Abstract

Diols represent a structurally diverse class of compounds with considerable biological and functional significance. Herein, we describe the synthesis of 1,1-bis(4-ethylphenyl)propan-1,2-diol (BEPP) via a Grignard reaction. The structure of BEPP was unambiguously elucidated by ¹H and ¹³C nuclear magnetic resonance (NMR), heteronuclear multiple-bond correlation (HMBC), high-resolution mass spectrometry (HRMS), and infrared (IR) spectroscopy.

1. Introduction

1,2-Diols are versatile organic compounds whose polar functionality, consisting of two hydroxy groups, plays a crucial role in hydrophilic interactions, including intra- and intermolecular hydrogen bonding. Consequently, 1,2-diols are employed in a wide range of industrial products, such as non-toxic antifreezes [1], moisturizers [2], surfactants [3], polyester monomers [4], preservatives [5], dye additives [6], cleaning agents [7], cosmetics [8], and food products [9]. Among these compounds, 1,1-diphenylpropan-1,2-diol (DPPD, (1); Chart 1) has been synthesized and studied for diverse applications, for example, as a stereo-inducing agent in Diels–Alder [10] and glyoxylate–ene reactions [11], and as a chiral host for the formation of inclusion complexes [12,13,14,15]. In contrast, its applications in medicinal chemistry have been limited to a single report in which ferrocene acetals exhibited moderate anticancer activity against T47D and MCF7 cell lines [16]. After remaining largely obscure for a decade, DPPD re-emerged during the COVID-19 pandemic when molecular modeling studies suggested that DPPD (1) and some of its congeners (2–5, Chart 1) might interact with the SARS-CoV-2 spike glycoprotein and inhibit its activity [17].

The Department of Chemistry, Faculty of Science, Kyushu University annually accepts approximately four outstanding high school students for a summer program in which selected participants conduct university-level research (the “Excellent Student in Science Project”). One of the authors (I.H., a high school student) developed an interest in organic chemistry through work with K.T. and undertook the synthesis of a p-ethyl derivative of 1 as a new entry into this medicinally important class of compounds. Compound 6, the p-ethyl derivative, was selected primarily for two reasons: the limited budget available and the expectation of few potential side reactions.

2. Results and Discussion

The synthesis was performed according to a reported procedure [10], substituting phenylmagnesium bromide with 4-ethylphenylmagnesium bromide (8). In this study, the less expensive racemic (±)-ethyl lactate was also used as the substrate to investigate the physical properties of the racemic compound (Scheme 1).

For the preparation of the Grignard reagent, a small amount of neat bromide 7 was initially added to a suspension of magnesium to facilitate initiation. Once the spontaneous exothermic reaction commenced, a dilute solution of bromide 7 was added dropwise to afford the corresponding Grignard reagent 8. Next, (±)-ethyl lactate in THF was added to the Grignard reagent 8 at room temperature. TLC analysis indicated formation of the major product; however, after work-up, the crude material remained a syrup even after attempted trituration with cold hexane. By contrast, the analogous reaction of (−)-ethyl lactate with phenylmagnesium bromide afforded a colorless solid. Under the suspicion that the ethyl groups in 6 and/or the racemic nature of the product impeded crystallization, the crude material was purified by silica-gel column chromatography. This procedure furnished the pure diol 6 in 96% yield.

The structure of compound 6 was elucidated by comprehensive spectroscopic analysis. The IR spectrum displayed a broad absorption band at ν = 3441 cm⁻¹, characteristic of O–H stretching vibrations and consistent with the presence of a vicinal diol moiety. Additional absorption bands were observed at ν = 3023, 2964, and 2931 cm⁻¹, corresponding to aromatic and aliphatic C–H stretching modes, respectively (Figure S1, see Supplementary Materials). HRMS (ESI-TOF) of the compound showed an m/z value of 307.1679, in excellent agreement with the calculated value for [M + Na]⁺ ([C₁₉H₂₄NaO₂]⁺, 307.1669; see Figure S2). These results strongly support the formation of the target diol 6; however, to obtain more definitive evidence, two-dimensional (2D) NMR spectroscopic analysis was performed.

In the ¹H NMR spectrum, a doublet at δ 1.11 ppm was assigned to the terminal methyl group of the propyl chain (H1), supported by strong HMBCs with C2 and C3 (Figure S7) as well as a clear COSY correlation with the adjacent methine proton H2 (Figure S5). Two sets of methyl protons from the ethyl substituents (H9 and H9′) resonated at δ 1.19 and 1.21 ppm and exhibited HMBCs with a methylene carbon (C8) and an aromatic carbon (C7). The corresponding methylene protons of the ethyl substituents (H8 and H8′) appeared as two quartets at δ 2.59 and 2.62 ppm and showed cross-peaks with C9 and C9′ (δ 15.5 ppm), C7 and C7′ (δ 142.7 and 143.2 ppm), and C6 and C6′ (δ 127.7 and 128.2 ppm) in the HMBC spectrum. The methine proton H2 appeared as a quartet at δ 4.80 ppm, and eight aromatic protons were observed between δ 7.10 and 7.53 ppm (Figure S3).

In the ¹³C NMR spectrum, the terminal methyl carbons (C9 and C9′) of the ethyl substituents appeared at δ 15.5 ppm, whereas the terminal methyl carbon (C1) of the propyl chain resonated at δ 16.7 ppm, both consistent with their aliphatic environments. The carbon C2 adjacent to the hydroxy group gave a signal at δ 71.9 ppm, while C3 resonated at δ 79.9 ppm and exhibited HMBCs with H5 and H5′. These assignments were fully supported by COSY and HSQC experiments (Figures S5 and S6). Collectively, comprehensive 1D and 2D NMR spectroscopic analyses unambiguously confirmed the structure of compound 6. This study also demonstrates that a high school student can successfully carry out a highly moisture-sensitive reaction and subsequent chromatographic purification to obtain the product in high yield. A key factor in this success was the effective initiation of the Grignard reagent formation by adding a small amount of bromide prior to dilution.

3. Materials and Methods

3.1. Instrumentation

The IR spectrum was recorded on a JASCO FT/IR-4100 spectrometer. ¹H and ¹³C NMR spectra were recorded on JEOL JNM-ECA 600 and 400 MHz spectrometers. Chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with reference to the internal residual solvent signals [¹H NMR: CDCl₃ (δ 7.26); ¹³C NMR: CDCl₃ (δ 47.3–48.1)]. The following abbreviations are used for signal multiplicities: s = singlet, d = doublet, t = triplet, q = quartet. The high-resolution mass spectrum (HRMS) was recorded on a Bruker microTOF II instrument.

3.2. 1,1-Bis(4-ethylphenyl)-1,2-propanediol

Magnesium turnings (1.80 g, 74.1 mmol) were placed in a 200 mL three-necked round-bottomed flask equipped with a magnetic stir bar, a Dimroth condenser, rubber septa, and a dropping funnel containing a small magnetic stir bar. A three-way stopcock and rubber septa were attached to the top of the condenser and dropping funnel, respectively, and a nitrogen-filled balloon was connected to the stopcock. The apparatus was evacuated and flushed with nitrogen. THF (5 mL) and 1-bromo-4-ethylbenzene (7, 9.00 mL, 65.3 mmol) were introduced into the dropping funnel by syringe and mixed using an external magnet. THF (5 mL) was then added to the magnesium, followed by the addition of bromide 7 (1.00 mL, 0.726 mmol) through the septum. Upon initiation of the exothermic reaction, the gently boiling mixture was diluted with THF (5 mL). The THF solution of 7 in the dropping funnel was added dropwise over 16 min to the reaction flask, and the funnel was rinsed with THF (1 mL). After complete addition, the mixture was stirred at room temperature for 2 h 45 min to afford a dark gray suspension, which was then warmed with a hair dryer to produce a gray Grignard solution (8).

Separately, a solution of (±)-ethyl lactate (2.33 mL, 20.3 mmol) in THF (9 mL) was prepared in the dropping funnel. This solution was added dropwise to the Grignard reagent over a period of 7 min, and the funnel was rinsed with THF (2 × 1 mL). The reaction mixture was stirred for an additional 30 min. After TLC indicated completion, the mixture was poured into 10% NH₄Cl aq. (90.0 mL, 168 mmol) in a 300 mL Erlenmeyer flask, stirred for 7 min, and extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (hexane/ethyl acetate = 30/1 → 6/1) to afford compound 6 (5.56 g, 19.6 mmol, 96%) as a colorless syrup.

R_f = 0.32 (Hexane/EtOAc = 5/1); IR (neat), 3441, 2964, 2931, 2872, 2360, 1906, 1714, 1509, 1455, 1372, 1312, 1265, 1168 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ: 7.52 (d, J = 8.4 Hz, 2H, arom), 7.34 (d, J = 8.0 Hz, 2H, arom), 7.18 (d, J = 8.4 Hz, 2H, arom), 7.11 (d, J = 8.0 Hz, 2H, arom), 4.79 (q, J = 6.0 Hz, 1H, CH₃CHOH), 2.62 (q, J = 7.6 Hz, 2H, PhCH₂CH₃), 2.59 (q, J = 7.6 Hz, 2H, PhCH₂CH₃), 1.21 (t, J = 7.6 Hz, 3H, PhCH₂CH₃), 1.19 (t, J = 7.6 Hz, 3H, PhCH₂CH₃) 1.11 (d, J = 6.0 Hz, 3H, CH₃CHOH) ppm; ¹³C NMR (150 MHz, CDCl₃) δ: 143.2, 143.1, 143.6, 143.5, 128.2, 127.7, 126.3, 125.6, 79.9, 71.9, 28.5, 16.7, 15.5 ppm; HRMS (ESI-TOF) m/z [M + Na]⁺ calcd for C₁₉H₂₄NaO₂ = 307.1669, found 307.1679.

4. Conclusions

In conclusion, 1,1-bis(4-ethylphenyl)-1,2-propanediol (6) was successfully synthesized by a high school student via a moisture-sensitive Grignard reaction. The pure product 6 was obtained as a colorless viscous oil. Further studies on the properties and potential applications of this compound are currently underway in our laboratory.