(E)-2-(1,3-Diphenylallyl)-3,5-dimethoxyphenol

Abstract

The synthesis of (E)-2-(1,3-diphenylallyl)-3,5-dimethoxyphenol is described by means of the reaction of 3,5-dimethoxyphenol with (E)-1,3-diphenylprop-2-en-1-ol in 1,1,1,3,3,3-hexafluoroispropanol (HFIP), which acts as a solvent and reaction promoter. The reaction proceeds smoothly to afford the mentioned compound in high yield under a metal and additive-free procedure. The corresponding allylated phenol has been fully characterized.

1. Introduction

The allylation reaction of electron-rich aromatics, such as phenol, in a Friedel–Crats-type reaction is a well-known transformation in organic synthesis [1,2,3]. However, this procedure normally requires the use of allylic substrates bearing a good leaving group, which are normally derived from alcohols, such as tosylates, carbonates, acetates, or halides. More recently, the use of alcohols as allylation substrates has also been achieved [4]. However, in both cases, the presence of a Brønsted or Lewis acid together with additives is frequently required in order to reach good yields (Scheme 1a). Thus, the overall process generates a stoichiometric amount of waste. Therefore, a much more attractive strategy from a practical, economical, and environmental point of view would be the direct use of alcohols without the need of such promoters and additives to carry out this transformation, generating water as the only by-product [5].

With the aim of expanding the applicability of our ongoing project about the use of fluorinated alcohols as solvents and promoters of chemical transformation [6,7,8], we envisioned the use of such alcohols to carry out the above-mentioned transformation (Scheme 1b). This idea arose not only because of the unique chemical and physical properties (such as a high hydrogen bond donor ability, low nucleophilicity, high polarity and ionizing power values, and a slight Brønsted acidity) of fluorinated alcohols [9,10,11], but also because they have been shown to be able to promote the nucleophilic substitution reaction onto the so-called activated alcohols (such as benzylic and allylic alcohols) [12,13].

2. Results

The synthesis of phenol 3 was achieved following a well-established methodology developed within the group [12]. Thus, (E)-1,3-diphenylprop-2-en-1-ol (1) and 3,5-dimethoxyphenol (2) were allowed to react for 15 h at 50 °C using 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a solvent and reaction promoter (Scheme 2). The solvent was then evaporated and, after purification by column chromatography, compound 3 was obtained in an 81% yield. The high regioselectivity of the reaction is also noteworthy, since the adduct 3 obtained from the attack of the para position of the OH in compound 2 was formally the sole observed (≥90%).

It is important to remark that other polar molecules such as H₂O or MeOH, which also have an important hydrogen bond donor ability, failed in this reaction, and no desired product 3 was observed. Contrarywise, when 2,2,2-trifluoroethanol (TFE) was employed, good conversion (81% by GC-MS) was also reached. However, in this case, a mixture of 5/1 between the formation of phenol 3 and ether 4 (Figure 1) was observed by analysis of GC-MS and NMR from the crude. The formation of this compound in this solvent could be ascribed by the lower acidity of this alcohol, which can act as a “base” in front of the phenol 2, hence allowing the formation of the nucleophilic phenolate. This situation would not occur in HFIP, where it is more acidic than phenol 2.

Finally, an S_N1-type process is proposed as a reaction mechanism (Scheme 3). Thus, firstly, an HFIP-mediated dehydration of allylic alcohol 1 would take place, rendering the quite stable delocalized allylic cation A. Then, the nucleophilic attack of 3,5-dimethoxyphenol (2) in a Friedel–Crafts type reaction onto this intermediate would take place. Finally, after rearomatization, the corresponding product 3 would be obtained.

3. Materials and Methods

All reagents and solvents were purchased from commercial suppliers and used without further purification. NMR spectra were performed on a Bruker AV-400 (Bruker Corporation, Karlsruhe, Germany) using CDCl₃ as solvent. Low-resolution mass spectra (MS) were recorded in the electron impact mode (EI, 70 eV, He as carrier phase) using an Agilent GC/MS 5973 Network Mass Selective Detector spectrometer apparatus equipped with an HP-5MS column (Agilent Technologies, 30 m × 0.25 mm), with fragment ions given in m/z with relative intensities (%) in parentheses. High-resolution mass spectra (HRMS) were obtained on an Agilent 7200 Quadrupole–Time of Flight apparatus (Q-TOF) (Agilent Technologies, Palo Alto, CA, USA), with the ionization employed being electron impact (EI). IRs were recorded on a JASCO FT-IR 4100 LE Pike Miracle ATR (Jasco Inc., Jasco Analítica Spain, Madrid, Spain) and only the structurally most relevant peaks are listed. Analytical TLC was performed on Merck silica gel plates and the spots visualized with UV light at 254 nm (Merck Millipore, Billerica, MA, USA). Flash chromatography employed Merck silica gel 60 (0.040–0.063 mm).

General procedure for the HFIP-promoted synthesis of phenol 3.

In a capped tube, onto a mixture of (E)-1,3-diphenylprop-2-en-1-ol (1, 0.25 mmol) and 3,5-dimethoxyphenol (2, 0.5 mmol, 2 equiv.), HFIP (250 μL) was added in one portion. The reaction was then stirred at 50 °C for 15 h. After this time, solvent was evaporated, and the crude material was directly purified by flash chromatography.

(E)-2-(1,3-diphenylallyl)-3,5-dimethoxyphenol (3):

Slightly yellow sticky oil; purification by flash chromatography (hexane/EtOAc), 88% yield; R_f = 0.74 (hexane/ethyl acetate 3/2); IR (ATR): ν = 3247, 3027, 2962, 2840, 1601, 1494, 1455, 1205, 1147, 1097 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.47–7.41 (m, 2H), 7.38–7.30 (m, 6H), 7.29–7.21 (m, 2H), 6.87 (dd, J = 16.0, 6.9 Hz, 1H), 6.48 (dd, J = 16.0, 1.5 Hz, 1H), 6.19 (d, J = 2.4 Hz, 1H), 6.11 (d, J = 2.4 Hz, 1H), 5.57 (dd, J = 6.9, 1.2 Hz, 1H), 5.33 (s, 1H), 3.80 (s, 6H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 160.2, 158.7, 156.0, 142.1, 137.1, 132.1, 130.6, 128.7, 128.5, 127.9, 127.4, 126.6, 126.4, 109.5, 94.6, 91.9, 55.9, 55.3, 42.3 ppm; MS (EI): m/z 346 (M+, 100%), 347 (25), 329 (15), 315 (36), 255 (68), 241 (31), 192 (56), 167 (46), 91 (42); HRMS calcd for C₂₃H₂₂O3: 346,1569; found: 346.1559 (See Supplementary Materials).

4. Conclusions

In conclusion, we have herein described the synthesis of (E)-2-(1,3-diphenylallyl)-3,5-dimethoxyphenol (3) in a metal- and additive-free strategy by using 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a solvent and promoter in the reaction between (E)-1,3-diphenylprop-2-en-1-ol (1) and 3,5-dimethoxyphenol (2). The corresponding product was obtained in high yield under smooth reaction conditions. In addition, the implemented process possesses a high atom economy, generating water as a by-product.