One-Pot Alkylation–Sulfonylation of Diphenol ^†

Abstract

The selective derivatization of the hydroxyl group in phenols is of paramount importance in synthetic chemistry. Alcohol was employed as the alkylating agent for converting phenol to alkyl aromatic ethers mediated by sulfonyl chloride-potassium carbonate. Diphenol underwent a one-pot alkylation–sulfonylation in the alcohol–sulfonyl chloride-K₂CO₃ system. This process enabled the non-symmetrical derivatization of phenolic hydroxyl groups in diphenols.

1. Introduction

Phenolic hydroxyl group, occurring in various pharmaceutical and natural molecules, has been considered as an efficient skeleton or functional group for the derivation of aromatic moiety [1]. Due to the broad synthetic applications and highly sensitive reactivities, controlling the selectivity of protection and derivatization of hydroxyl groups is an indispensable challenge to achieve the desired chemical conversion [2]. Alkylation of the phenolic -OH group is not only a simple functional group transformation [3,4], but also produces alkyloxy groups that are key scaffolds dictating the properties of the final molecules [5,6]. However, the common alkylation reagents, such as halides, alkyl sulfates, and sulfonates, have been limited due to their environmental toxicity, potential danger to health [7,8].

In the previous work, alkyl sulfonyloxyphenyl ether could be synthesized selectively via a sequential procedure of monodesulfonation of diphenol bissulfonate alkylation [9]. Observation of the in situ formation of phenoxy anion indicated the feasibility of direct alkylation of the phenolic hydroxyl group. Herein, methods for the alkylation of phenolic hydroxyl groups in phenols and the alkylation–sulfonylation of diphenols are described, utilizing alcohols as alkylating agents in the presence of sulfonyl chloride.

2. Results and Discussion

2.1. Alkylation of Phenol with Alcohols

To evaluate the feasibility of the alkylation using alcohols as alkylating agents, the model substrate o-bromophenol was treated with 2.5 mL of methanol, excess potassium carbonate, and p-toluenesulfonyl chloride (p-TsCl) based on prior work [9]. The mixture was subjected to ultrasound-assisted reaction for 6 h. TLC monitoring indicated that the desired alkylated product was not obtained. Subsequently, the reaction was carried out under reflux heating for 5 h, after which TLC analysis showed complete consumption of the starting phenol. Following standard workup, the corresponding methylated product, o-bromoanisole (1a), was obtained (Figure 1). Substrate scope investigation demonstrated that this reaction condition could be applied to the alkylation of various phenols, providing an effective approach for the synthesis of a series of alkyl aromatic ethers 1a𠄲d using alcohols as alkylating agents (Figure 2).

As illustrated in Figure 2, the sulfonyl chloride-mediated alkylation of phenols with alcohols is a viable strategy (Figure 2). A variety of phenols bearing diverse substituents, including sensitive groups such as formyl and nitro, could be converted to alkylated products under standard conditions, highlighting the system’s broad functional group tolerance.

2.2. One-Pot Alkylation–Sulfonylation of Diphenol

Based on the results of the sulfonyl chloride-mediated alkylation of phenols with alcohols, resorcinol was employed as the model substrate to investigate the reactivity and selectivity of its two phenolic hydroxyl groups under the alcohol–TsCl–K₂CO₃ system. Notably, the formation of 3-methoxyphenyl sulfonate was observed in 60% yield. This indicated that, under the current conditions, the two phenolic hydroxyl groups of resorcinol underwent alkylation and sulfonylation, respectively (Figure 3).

In this weakly basic reaction system, the alcohol served a dual role as both the alkylating agent and the solvent.

3. Materials and Methods

¹H and ¹³C NMR spectra were recorded on a Bruker Avance DMX500 (Bruker Corporation, Karlsruhe, Germany) in CDCl₃ solutions and with tetramethylsilane as an internal standard. Melting points were recorded on the Micro melting point meter X5.

3.1. 1-Bromo-2-Methoxybenzene 1a [10]

Colorless oil, 75% isolated yield; ¹H NMR (500 MHz, CDCl₃) δ 7.52 (dd, J = 7.9, 1.6 Hz, 1H), 7.26 (ddd, J = 9.0, 1.6, 0.7 Hz, 1H), 6.88 (dd, J = 8.2, 1.3 Hz, 1H), 6.80 (td, J = 7.7, 1.4 Hz, 1H), 3.85 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 155.9, 133.4, 128.6, 121.8, 112.0, 111.7, 56.2.

3.2. 1-Bromo-2-Ethoxybenzene 1b [11]

Colorless oil, 88% isolated yield; ¹H NMR (500 MHz, CDCl₃) δ 7.53 (dd, J = 7.9, 1.6 Hz, 1H), 7.27–7.25 (ddd, J = 7.4, 1.6, 0.8 Hz, 1H), 6.82 (td, J = 7.7, 1.4 Hz, 1H), 6.81 (m, 1H), 4.09 (t, J = 7.1 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 155.3, 133.4, 128.4, 121.7, 113.3, 112.2, 64.8, 14.7.

3.3. 3,4-Dimethoxybenzaldehyde 1c [12]

White solid, 85% isolated yield; m.p. 41–42 °C; ¹H NMR (500 MHz, CDCl₃) δ 9.86 (s, 1H), 7.46 (dd, J = 8.2, 1.8 Hz, 1H), 7.42 (d, J = 1.8 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 190.9, 154.5, 149.6, 130.2, 126.9, 110.4, 108.9, 56.2, 56.0.

3.4. 1-(2-Methylallyl)oxy)-2-Nitrobenzene 1d [13]

Light green oil, 65% isolated yield; ¹H NMR (400 MHz, CDCl₃) δ 7.86 (dd, J = 8.1 Hz, 1.7 Hz, 1H), 7.52–7.47 (m, 1H), 7.08–7.06 (m, 1H), 7.05–7.01 (m, 1H),5.14–5.01 (m, 2H), 4.56 (s, 2H), 1.82 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 151.7, 139.6, 134.1, 125.8, 120.5, 114.8, 113.5, 72.6, 19.3.

3.5. 3-Methoxyphenyl 4-Methylbenzenesulfonate 2a [9]

White solid, 80% isolated yield; m.p. 54–55 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.72 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.16 (t, J = 8.2 Hz, 1H), 6.78 (dd, J = 8.3, 2.2 Hz, 1H), 6.59–6.54 (m, 2H), 3.72 (s, 3H), 2.45 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 160.4, 150.5, 145.3, 132.5, 129.9, 129.7, 128.9, 114.3, 113.1, 108.2, 55.5, 21.7.

3.6. 3-Ethoxyphenyl 4-Methylbenzenesulfonate 2b [9]

Colorless oil, 65% isolated yield; ¹H NMR (500 MHz, CDCl₃) δ 7.63 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.05 (t, J = 8.3 Hz, 1H), 6.67 (ddd, J = 8.4, 2.4, 0.7 Hz, 1H), 6.47 (t, J = 2.3 Hz, 1H), 6.43 (ddd, J = 8.1, 2.2, 0.8 Hz, 1H), 3.83 (q, J = 8.0 Hz, 2H), 2.35 (s, 3H), 1.27 (t, J = 8.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 159.8, 150.5, 145.3, 132.5, 129.8, 129.7, 128.5, 114.1, 113.6, 108.7, 63.7, 21.7, 14.6.

4. Conclusions

A green protocol for the O-alkylation of phenols was developed, utilizing alcohols as alkylating agents in the presence of a weak base (K₂CO₃) and a sulfonyl chloride. This system enabled highly selective alkylation–sulfonylation of diphenols, allowing the introduction of distinct groups onto different oxygen atoms. This strategy provided a novel approach for the non-symmetric derivatization of phenolic hydroxyl groups. The successful synthesis of allyl ether 1d not only offered a versatile handle for arene functionalization via Claisen rearrangement but also presented a potential synthetic route to natural products containing allyl aryl ether motifs, such as eugenol. This method employed low-toxicity, readily available alcohols and mild K₂CO₃, offering a green, efficient, and operationally simple alternative.