Convenient Method of Synthesizing Aryloxyalkyl Esters from Phenolic Esters Using Halogenated Alcohols

A facile one-pot synthetic method of building aryloxyalkyl esters was developed using various types of phenolic esters with halogenated alcohols. The ready availability of both starting materials, coupled with the required simple experimental technique, enables the current synthetic method of producing aryloxyalkyl esters in a fast and efficient way. It is noteworthy that acyl transfer was demonstrated in this reaction.

To further the interest in the modification of flavonoids [32], we tried to synthesize 7-(3-hydroxypropoxy) wogonin by modifying the 7-acetate of wogonin with 3-bromoethanol. Unfortunately, the desired product (7-hydroxypropoxy wogonite) was rarely obtained. Aryloxyalkyl ester (3ba), however, was serendipitously obtained through the reaction displayed in Scheme 2. Previous study has indicated that aryloxyalkyl esters were important moieties in organic syntheses, primarily due to ubiquitous applications in pharmaceuticals, electrophosphorescent materials, plasticizers, and luminescent materials [33][34][35][36]. The preparation of aryloxyalkyl esters was mainly though a two-step process: Introduction of an aliphatic chain, followed by esterification with carboxylic acids or anhydrides [37,38]. Undoubtedly, the efficiency of these protocols was restricted from the view of step economy for the synthesis of a variety of substituents. Herein, we disclose a convenient synthesis of aryloxyalkyl esters from phenolic esters with halogenated alcohol. To further the interest in the modification of flavonoids [32], we tried to synthesize 7-(3hydroxypropoxy) wogonin by modifying the 7-acetate of wogonin with 3-bromoethanol. Unfortunately, the desired product (7-hydroxypropoxy wogonite) was rarely obtained. Aryloxyalkyl ester (3ba), however, was serendipitously obtained through the reaction displayed in Scheme 2. Previous study has indicated that aryloxyalkyl esters were important moieties in organic syntheses, primarily due to ubiquitous applications in pharmaceuticals, electrophosphorescent materials, plasticizers, and luminescent materials [33][34][35][36]. The preparation of aryloxyalkyl esters was mainly though a two-step process: Introduction of an aliphatic chain, followed by esterification with carboxylic acids or anhydrides [37,38]. Undoubtedly, the efficiency of these protocols was restricted from the view of step economy for the synthesis of a variety of substituents. Herein, we disclose a convenient synthesis of aryloxyalkyl esters from phenolic esters with halogenated alcohol. Scheme 2. The new method to synthesize aryloxyalkyl ester.

Results and Discussion
First, we investigated the effects of reaction parameters in this new aryloxyalkyl esterification reaction (Table 1). Phenyl acetate (1a) was chosen as a model substrate and subjected to a preliminary condensation condition by using 3-bromoethanol (2a) (1.05 equiv) and K2CO3 (1.5 equiv) in commercial grade acetone under reflux for 6 h. Gratifyingly, the phenolic ester extension reaction proceeded smoothly, with concomitant cleavage of the ester bond and construction of the ether bond, delivering 3-phenoxypropyl acetate (3aa) in 59% isolated yield (entry 1). Changing the solvent from acetone to tetrahydrofuran or acetonitrile resulted in inferior results (entries 2 and 3). However, when N,N-dimethylformamide (DMF) was used as the solvent, 3aa was obtained in comparably good conversions (entry 4). By increasing the amount of potassium carbonate, further enhancive conversion was observed, which have been used to establish the optimal conditions (entry 5). No reaction was observed without a base (entry 6), whereas a weak base depressed the conversion (entry 7), indicating that the base could break the ester bond. Two other bases, i.e., Cs2CO3 and NaH, afforded the products (entries 8 and 9) with similar yields to entry 5. When NaOH was used as the base, only a trace amount of the target product, 3aa, was detected by high performance liquid chromatography (HPLC), instead of generating a large amount of 3-phenoxypropan-1-ol. (entry 10).

Scheme 2.
The new method to synthesize aryloxyalkyl ester.

Results and Discussion
First, we investigated the effects of reaction parameters in this new aryloxyalkyl esterification reaction (Table 1). Phenyl acetate (1a) was chosen as a model substrate and subjected to a preliminary condensation condition by using 3-bromoethanol (2a) (1.05 equiv) and K 2 CO 3 (1.5 equiv) in commercial grade acetone under reflux for 6 h. Gratifyingly, the phenolic ester extension reaction proceeded smoothly, with concomitant cleavage of the ester bond and construction of the ether bond, delivering 3-phenoxypropyl acetate (3aa) in 59% isolated yield (entry 1). Changing the solvent from acetone to tetrahydrofuran or acetonitrile resulted in inferior results (entries 2 and 3). However, when N,N-dimethylformamide (DMF) was used as the solvent, 3aa was obtained in comparably good conversions (entry 4). By increasing the amount of potassium carbonate, further enhancive conversion was observed, which have been used to establish the optimal conditions (entry 5). No reaction was observed without a base (entry 6), whereas a weak base depressed the conversion (entry 7), indicating that the base could break the ester bond. Two other bases, i.e., Cs 2 CO 3 and NaH, afforded the products (entries 8 and 9) with similar yields to entry 5. When NaOH was used as the base, only a trace amount of the target product, 3aa, was detected by high performance liquid chromatography (HPLC), instead of generating a large amount of 3-phenoxypropan-1-ol. (entry 10).  Next, we investigated the application range of this reaction by using a variety of phenol esters and bromoalkyl alcohols under the optimized conditions: 0.5 mmol of 1 and 0.525 mmol of 2 in DMF at 80 °C for 6 h under an Ar atmosphere (Scheme 3). Both electron-rich and electron-withdrawing substituents produced the desired aryloxyalkyl esters in good yields (3ab and 3ac). It is noteworthy that substrates bearing functional groups (e.g., aldehyde, ketone, nitrile, or halogen) also showed good performance in this reaction (3ad-ai). To further extend the utility of this reaction, we then put our effort to the types of acid esters from the common acetates. It was observed that various substituted phenyl benzoates reacted well, leading to the formation of the corresponding aryloxyalkyl esters (3aj-an) in yields of 47-71%. Notably, chlorophenylacetate moiety was tolerated, providing the target product, 3ao, in 45% yield. Delightfully, we found that even cinnamate derivatives under the reaction conditions could give the corresponding products (3ap and 3aq) in moderate to good yields (with increased base loading). Changing the starting material from phenyl ester to alkyl ester, however, resulted in a large amount of alkyl ester remaining and no target product, which might be because the ester bond of alkyl ester was difficult to be broken (see Scheme S1 in Supplementary Materials).
Furthermore, the diversity of halohydrins was also studied (Scheme 4). 2-Bromoethanol (2b), 4bromobutanol (2c), and 5-bromopentanol (2d) performed similarly to produce the corresponding products, 3ar-ax, in moderate to high yields. For the synthesis of compound 3ar, the usage of 2bromoethanol, 2-chloroethanol, or 2-iodoethanol contributed similar yields, wherein the use of 2iodoethanol slightly increased the yield of 3ar. The longer alkyl chain resulted in lower yield. The scope of the present investigation was extended to flavone derivatives. Baicalein and wogonin were applicable under our reaction conditions, providing the target products (3ay, 3az and 3ba) in moderate yields. Next, we investigated the application range of this reaction by using a variety of phenol esters and bromoalkyl alcohols under the optimized conditions: 0.5 mmol of 1 and 0.525 mmol of 2 in DMF at 80 • C for 6 h under an Ar atmosphere (Scheme 3). Both electron-rich and electron-withdrawing substituents produced the desired aryloxyalkyl esters in good yields (3ab and 3ac). It is noteworthy that substrates bearing functional groups (e.g., aldehyde, ketone, nitrile, or halogen) also showed good performance in this reaction (3ad-ai). To further extend the utility of this reaction, we then put our effort to the types of acid esters from the common acetates. It was observed that various substituted phenyl benzoates reacted well, leading to the formation of the corresponding aryloxyalkyl esters (3aj-an) in yields of 47-71%. Notably, chlorophenylacetate moiety was tolerated, providing the target product, 3ao, in 45% yield. Delightfully, we found that even cinnamate derivatives under the reaction conditions could give the corresponding products (3ap and 3aq) in moderate to good yields (with increased base loading). Changing the starting material from phenyl ester to alkyl ester, however, resulted in a large amount of alkyl ester remaining and no target product, which might be because the ester bond of alkyl ester was difficult to be broken (see Scheme S1 in Supplementary Materials).
Furthermore, the diversity of halohydrins was also studied (Scheme 4). 2-Bromoethanol (2b), 4-bromobutanol (2c), and 5-bromopentanol (2d) performed similarly to produce the corresponding products, 3ar-ax, in moderate to high yields. For the synthesis of compound 3ar, the usage of 2-bromoethanol, 2-chloroethanol, or 2-iodoethanol contributed similar yields, wherein the use of 2-iodoethanol slightly increased the yield of 3ar. The longer alkyl chain resulted in lower yield. The scope of the present investigation was extended to flavone derivatives. Baicalein and wogonin were applicable under our reaction conditions, providing the target products (3ay, 3az and 3ba) in moderate yields.
A series of control experiments were carried out to elucidate the reaction mechanism (Scheme 5). Firstly, as 3-methyl-2-butenyl bromide (2e) was used to substitute 3-bromoethanol (2a), the product, 1-isopentenyl naphthol (4), was obtained instead of the target product (Scheme 5A). Secondly, when the amount of 3-bromopropanol (2a) was increased from 1.05 equivalents to 4 equivalents, 3-(2-naphthoxy)propan-1-ol (5) was obtained, which suggested that the generated acetyl A series of control experiments were carried out to elucidate the reaction mechanism (Scheme 5). Firstly, as 3-methyl-2-butenyl bromide (2e) was used to substitute 3-bromoethanol (2a), the product, 1-isopentenyl naphthol (4), was obtained instead of the target product (Scheme 5A). Secondly, when the amount of 3-bromopropanol (2a) was increased from 1.05 equivalents to 4 equivalents, 3-(2-naphthoxy)propan-1-ol (5) was obtained, which suggested that the generated acetyl reactive intermediate might not be selective in reacting with the alcoholic hydroxyl group (Scheme 5B). No reaction was observed when no potassium carbonate was used, indicating that the phenolic ester bond was firstly broken by potassium carbonate. Further, sulfonates and aromatic amides were found to be incompatible with the reaction conditions and resulted in nothing even under refluxing conditions, suggesting that potassium carbonate could not attack the carbonyl group of the acylamine bonds because the polarization of the carbonyl group is weaker compared with the ester carbonyl group (Scheme 5C,D). However, when the strong base, NaH, was used, the deprotonation of 2a formed an oxygen negative intermediate, which would attack the carbonyl group at a high temperature. No reaction was observed when no potassium carbonate was used, indicating that the phenolic ester bond was firstly broken by potassium carbonate. Further, sulfonates and aromatic amides were found to be incompatible with the reaction conditions and resulted in nothing even under refluxing conditions, suggesting that potassium carbonate could not attack the carbonyl group of the acylamine bonds because the polarization of the carbonyl group is weaker compared with the ester carbonyl group (Scheme 5C,D). However, when the strong base, NaH, was used, the deprotonation of 2a formed an oxygen negative intermediate, which would attack the carbonyl group at a high temperature.

Scheme 5.
Control experiments to investigate the mechanism.
Based on the above experiments, we propose a plausible mechanism as shown in Scheme 4. Initially, in the presence of potassium carbonate (Scheme 6A), phenyl acetate (1a) is transformed into phenol salt 8 and intermediate 9, exhibiting similar chemical properties with anhydrides [39]. Subsequently, the two-step reaction is carried out separately. On one hand, phenol salt 8 is allowed to react with bromopropanol to form a phenolic ester by SN2 nucleophilic substitutions. On the other hand, propanol OH with a nucleophilicity can attack the carbonyl carbon of the intermediate 9, and release a molecule of potassium bicarbonate to form an ester bond. To verify the speculation that this reaction had two separate steps, intermediate 5 was employed to react with acetic anhydride (1 equiv), which could be transformed to 3ah in an isolated yield of 73%. The 1-butanol (2f) was used to react with substrate 1v under the standard conditions, resulting in the products 10 and 11. Based on these observations, we came to the conclusion that the oxygen atom of the alcoholic hydroxyl group attacked the carbonyl carbon atom to form the ester bond. Additionally, when NaH was used as a base, the reaction might be carried out according to the following route (Scheme 6B): In the presence of NaH, 3-bromopropanol (2a) deprotonated to form the oxygen negative intermediate, 12, which then nucleophilically attacked the phenolic ester bond of the compound, 1a, to form the intermediates, 13 and 14. Subsequently, intermediates 13 and 14 underwent a SN2 nucleophilic substitution reaction to produce the target compound, 3aa.

Scheme 5. Control experiments to investigate the mechanism.
Based on the above experiments, we propose a plausible mechanism as shown in Scheme 4. Initially, in the presence of potassium carbonate (Scheme 6A), phenyl acetate (1a) is transformed into phenol salt 8 and intermediate 9, exhibiting similar chemical properties with anhydrides [39]. Subsequently, the two-step reaction is carried out separately. On one hand, phenol salt 8 is allowed to react with bromopropanol to form a phenolic ester by S N 2 nucleophilic substitutions. On the other hand, propanol OH with a nucleophilicity can attack the carbonyl carbon of the intermediate 9, and release a molecule of potassium bicarbonate to form an ester bond. To verify the speculation that this reaction had two separate steps, intermediate 5 was employed to react with acetic anhydride (1 equiv), which could be transformed to 3ah in an isolated yield of 73%. The 1-butanol (2f) was used to react with substrate 1v under the standard conditions, resulting in the products 10 and 11. Based on these observations, we came to the conclusion that the oxygen atom of the alcoholic hydroxyl group attacked the carbonyl carbon atom to form the ester bond. Additionally, when NaH was used as a base, the reaction might be carried out according to the following route (Scheme 6B): In the presence of NaH, 3-bromopropanol (2a) deprotonated to form the oxygen negative intermediate, 12, which then nucleophilically attacked the phenolic ester bond of the compound, 1a, to form the intermediates, 13 and 14. Subsequently, intermediates 13 and 14 underwent a S N 2 nucleophilic substitution reaction to produce the target compound, 3aa.
group attacked the carbonyl carbon atom to form the ester bond. Additionally, when NaH was used as a base, the reaction might be carried out according to the following route (Scheme 6B): In the presence of NaH, 3-bromopropanol (2a) deprotonated to form the oxygen negative intermediate, 12, which then nucleophilically attacked the phenolic ester bond of the compound, 1a, to form the intermediates, 13 and 14. Subsequently, intermediates 13 and 14 underwent a SN2 nucleophilic substitution reaction to produce the target compound, 3aa. Given the low selectivity of the intermediate 9 reacting with the alcoholic hydroxyl group, we wondered whether the hydroxyl group in the own phenolic ester structure would also be reactive substrates without additional halogenated alcohols. 5-Acetyl wogonin was used as a substrate to study the intramolecular nucleophilic substitution reaction (Scheme 7). Gratifyingly, the desired target product, 7-acetyl wogonin, was obtained in good yields without 5-acetyl wogonin remaining under standard conditions. A possible explanation for the acyl transfer phenomenon was that the acetyl group was detached from the 5-O-wogonin in the presence of potassium carbonate, subsequently attacked by the highly nucleophilic 7-OH of wogonin to give 7-acetyl wogonin. The reason might be the formation of the intramolecular hydrogen bond at 5-position with para-carbonyl group endowed it with weaker acidity than 7-OH of wogonin, leading the acetyl group to easily binding to 7-OH. Given the low selectivity of the intermediate 9 reacting with the alcoholic hydroxyl group, we wondered whether the hydroxyl group in the own phenolic ester structure would also be reactive substrates without additional halogenated alcohols. 5-Acetyl wogonin was used as a substrate to study the intramolecular nucleophilic substitution reaction (Scheme 7). Gratifyingly, the desired target product, 7-acetyl wogonin, was obtained in good yields without 5-acetyl wogonin remaining under standard conditions. A possible explanation for the acyl transfer phenomenon was that the acetyl group was detached from the 5-O-wogonin in the presence of potassium carbonate, subsequently attacked by the highly nucleophilic 7-OH of wogonin to give 7-acetyl wogonin. The reason might be the formation of the intramolecular hydrogen bond at 5-position with para-carbonyl group endowed it with weaker acidity than 7-OH of wogonin, leading the acetyl group to easily binding to 7-OH.

General
All reactions were monitored by thin layer chromatography (TLC) on WhatmanPartisil ® K6F TLC plates (silica gel 60 Å , 0.25 mm thickness, Qingdao Haiyang Chemical Plant, Qingdao, China) and visualized using a UV lamp (254 or 365 nm, Shanghai Guanghao Analysis Instrument Co., Ltd., Shanghai, China) or by use of one of the following visualization reagents: Products were isolated by column chromatography (Merck silica gel 100-200 mesh, Merck, Darmstadt, Germany). Yields refer to chromatographically and spectroscopically homogenous materials unless noted otherwise. 1 H-and 13 C-NMR spectra were recorded on Bruker 300 MHz spectrometers (Bruker, Karlsruhe, Germany).

General Procedure for the Aryloxyalkyl Esters from Phenolic Esters (3aa-3aq)
Phenyl esters 1a-1c (0.5 mmol) were loaded into a flask (10 mL). DMF (2 mL) and Cs2CO3 (488 mg, 1.5 mmol, 3.0 equiv) were then added, which was followed by the addition of 3-bromoethanol (2a, 0.525 mmol, 1.05 equiv). Then the reaction mixture was stirred at 80 °C for 6 h under an Ar atmosphere. After completion of the reaction, as confirmed by TLC, the reaction mixture was cooled down to room temperature and 10 mL of CH2Cl2 (DCM) and 10 mL of water were added. After separation of the dichloromethane layer from the water, the aqueous phase was extracted with CH2Cl2 (2 × 5 mL) again. The combined organic layers were then dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to yield the crude product. The crude product was purified

General
All reactions were monitored by thin layer chromatography (TLC) on WhatmanPartisil ® K6F TLC plates (silica gel 60 Å, 0.25 mm thickness, Qingdao Haiyang Chemical Plant, Qingdao, China) and visualized using a UV lamp (254 or 365 nm, Shanghai Guanghao Analysis Instrument Co., Ltd., Shanghai, China) or by use of one of the following visualization reagents: Products were isolated by column chromatography (Merck silica gel 100-200 mesh, Merck, Darmstadt, Germany). Yields refer to chromatographically and spectroscopically homogenous materials unless noted otherwise. 1 H-and 13 C-NMR spectra were recorded on Bruker 300 MHz spectrometers (Bruker, Karlsruhe, Germany).

General Procedure for the Aryloxyalkyl Esters from Phenolic Esters (3aa-3aq)
Phenyl esters 1a-1c (0.5 mmol) were loaded into a flask (10 mL). DMF (2 mL) and Cs 2 CO 3 (488 mg, 1.5 mmol, 3.0 equiv) were then added, which was followed by the addition of 3-bromoethanol (2a, 0.525 mmol, 1.05 equiv). Then the reaction mixture was stirred at 80 • C for 6 h under an Ar atmosphere. After completion of the reaction, as confirmed by TLC, the reaction mixture was cooled down to room temperature and 10 mL of CH 2 Cl 2 (DCM) and 10 mL of water were added. After separation of the dichloromethane layer from the water, the aqueous phase was extracted with CH 2 Cl 2 (2 × 5 mL) again. The combined organic layers were then dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum to yield the crude product. The crude product was purified by silica gel column chromatography to obtain the desired pure compound.

General Procedure for the Reaction of Halogenated Alcohols and Application to the Synthesis of Flavonoid Derivatives (3ar-3ba)
Phenyl esters 1a-1j (0.5 mmol) were loaded into a flask (10 mL). DMF (4 mL) and Cs 2 CO 3 (488 mg, 1.5 mmol, 3.0 equiv) were then added, which was followed by the addition of bromohydrin (0.525 mmol, 1.05 equiv). Then, the reaction mixture was stirred at 80 • C for 6 h under an Ar atmosphere. After completion of the reaction, as confirmed by TLC, the reaction mixture was cooled down to room temperature and 10 mL of EtOAc and 10 mL of water were added. After separation of the EtOAc layer from the water, the aqueous phase was extracted with EtOAc (2 × 5 mL) again. The combined organic layers were then dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum to yield the crude product. The crude product was purified by silica gel column chromatography to obtain the desired pure compound.

Control Experiments to
Investigate the Mechanism 2-((3-Methylbut-2-en-1-yl)oxy)naphthalene (4). Phenyl esters 1i (0.5 mmol) were loaded into a flask (10 mL). DMF (2 mL) and K 2 CO 3 (207 mg, 1.5 mmol, 3.0 equiv) were then added, which was followed by the addition of 3-methyl-2-butenyl bromide 2e (0.525 mmol, 1.05 equiv). Then, the reaction mixture was stirred at 80 • C for 6 h under an Ar atmosphere. After completion of the reaction, as confirmed by TLC, the reaction mixture was cooled down to room temperature and 10 mL of CH 2 Cl 2 and 10 mL of water were added. After separation of the dichloromethane layer from the water, the aqueous phase was extracted with CH 2 Cl 2 (2 × 5 mL) again. The combined organic layers were then dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum to yield the crude product. The crude product was purified by silica gel column chromatography with hexane/EtOAc (8:1 v/v) to afford the desired compound, 4 (CAS: 23676-18-8), as a slightly yellow solid (96 mg, 91% yield). 1  3-(Naphthalen-2-yloxy)propan-1-ol (5). Phenyl ester 1i (0.5 mmol) was loaded into a flask (10 mL). DMF (2 mL) and K 2 CO 3 (207 mg, 1.5 mmol, 3.0 equiv) were then added, which was followed by the addition of 3-bromo-1-propanol 2a (2.0 mmol, 4 equiv). Then, the reaction mixture was stirred at 80 • C for 6 h under an Ar atmosphere. After completion of the reaction, as confirmed by TLC, the reaction mixture was cooled down to room temperature and 10 mL of CH 2 Cl 2 and 10 mL of water were added.

Conclusions
In summary, we have developed a facile and unified one-pot synthesis to obtain aryloxyalkyl esters from readily available phenolic esters and suitable substituted halogenated alcohols, which helps to quickly build a diversity chain of aromatic alkyl esters. In the mechanistic studies, we discovered the acyl transfer mechanism and explained the reasons for the formation of aryloxyalkyl esters. However, for secondary alcohols or tertiary alcohols, the corresponding target compounds cannot be obtained under standard reaction conditions, which can be attributed to the large steric hindrance near the hydroxyl group affecting the nucleophilic substitution reaction (S N 2) of hydroxyl groups. In addition, secondary or tertiary alcohols are more likely to undergo elimination reactions under alkaline conditions. Further detailed mechanistic studies and applications will be reported in due course.