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Article

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

by
Xueyang Jiang
1,
Junting Zhou
1,
Yue Zhou
2,
Haopeng Sun
3,
Jian Xu
1,
Feng Feng
1,4,5,* and
Wei Qu
1,4,*
1
Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
2
Department of Pharmacy Administration & Clinical Pharmacy, Peking University, Beijing 100191, China
3
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
4
Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing 210009, China
5
Food and Drug Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, China
*
Authors to whom correspondence should be addressed.
Molecules 2018, 23(7), 1715; https://doi.org/10.3390/molecules23071715
Submission received: 22 June 2018 / Revised: 10 July 2018 / Accepted: 12 July 2018 / Published: 13 July 2018
(This article belongs to the Section Organic Chemistry)
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Abstract

:
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.

Graphical Abstract

1. Introduction

Phenols are typically protected by various groups to enhance their leaving ability in cross-coupling reactions [1,2,3]. Thus, phenols have usually been converted to their corresponding aryl C-O electrophiles, such as fluoroalkylsulfonates [4,5], sulfamates [6,7,8], sulfonates [9,10,11,12], carbonates [13,14,15], carbamates [16,17], ethers [18], phosphoramides, phosphonium salts, phosphates, and pivalates [19,20,21,22]. Besides the preferable availability of phenol derivatives, this method also proves to be cost-effective, as well as an efficient reaction route to form C-C bonds, C-N bonds, and C-H bonds (Scheme 1) [23,24,25,26,27,28]. Phenolic esters, a type of aryl C-O electrophiles, are considered as notable functional groups or protecting groups in organic synthesis, and can be found in various bioactive natural products, agrochemicals, pharmaceuticals, and functional polymers [29,30,31].
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.

2. 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).
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 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.
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.
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.

3. Materials and Methods

3.1. 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. 1H- and 13C-NMR spectra were recorded on Bruker 300 MHz spectrometers (Bruker, Karlsruhe, Germany).

3.2. 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 by silica gel column chromatography to obtain the desired pure compound.
3-Phenoxypropyl acetate (3aa). Compound 3aa (CAS: 58883-98-0) was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 200:1) to provide the pure compound (73 mg, 76%) as a colorless oil. 1H-NMR (300 MHz, CDCl3, δ ppm): 7.33 (t, J = 8.2 Hz, 2H), 6.93–6.99 (m, 1H), 6.93 (d, J = 8.6 Hz, 2H), 4.31 (t, J = 6.1 Hz, 2H), 4.07 (t, J = 6.1 Hz, 2H), 2.13–2.19 (m, 2H), 2.09 (s, 3H); 13C-NMR (75 MHz, CDCl3, δ ppm): 170.7, 158.2, 129.1, 120.3, 113.9, 63.6, 60.9, 28.1, 20.4; MS (ESI): m/z = 193.1 [M − H]−; Rf = 0.5 (DCM:MeOH 100:1).
3-(4-Methoxyphenoxy)propyl acetate (3ab). Compound 3ab was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 200:1) to provide the pure compound (71 mg, 64%) as a colorless oil. 1H-NMR (300 MHz, CDCl3, δ ppm): 6.85 (s, 4H, Ar-H), 4.27 (t, J = 6.1 Hz, 2H), 4.01 (t, J = 6.1 Hz, 2H), 3.78 (s, 3H, -OCH3), 2.08–2.14 (m, 2H), 2.07 (s, 3H, -COCH3); 13C-NMR (75 MHz, CDCl3, δ ppm): 196.8, 171.0, 162.6, 130.6, 130.4, 114.1, 64.6, 61.0, 28.4, 26.3, 20.9; HRMS (ESI): m/z calcd. for C12H17O4: 225.1121, found: 225.1119 [M + H]+; Rf = 0.5 (DCM:MeOH 100:1).
3-(4-Nitrophenoxy)propyl acetate (3ac). Compound 3ac (CAS: 99986-51-3) was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (96 mg, 81%) as a light yellow oil. 1H-NMR (300 MHz, CDCl3, δ ppm): 8.17 (d, J = 8.1 Hz, 2H), 6.5 (d, J = 8.1 Hz, 2H), 4.26 (t, J = 6.1 Hz, 2H), 4.14 (t, J = 6.1 Hz, 2H), 2.12–2.20 (m, 2H), 2.05 (s, 3H); 13C-NMR (75 MHz, CDCl3, δ ppm): 170.4, 163.2, 140.9, 125.3, 113.9, 64.7, 60.3, 27.8, 20.4; MS (ESI): m/z = 238.1 [M − H]−; Rf = 0.2 (DCM:MeOH 100:1).
3-(4-Formylphenoxy)propyl acetate (3ad). Compound 3ad was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 50:1) to provide the pure compound (54 mg, 49%) as a colorless oil. 1H-NMR (300 MHz, CDCl3, δ ppm): 9.83 (s, 1H, -CHO), 7.78 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 8.1 Hz, 2H), 4.11 (t, J = 6.1 Hz, 2H), 4.04 (t, J = 6.1 Hz, 2H), 2.02 (s, 3H, -COCH3), 1.77–1.89 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 190.3, 170.6, 163.4, 131.5, 129.3, 114.1, 67.1, 63.4, 24.7, 20.4; MS (ESI): m/z = 221.1 [M − H]−; HRMS (ESI): m/z calcd. for C12H15O4: 223.0965, found: 223.0961 [M + H]+; Rf = 0.3 (DCM:MeOH 50:1).
3-(4-Acetylphenoxy)propyl acetate (3ae). Compound 3ae (CAS: 146274-20-6) was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (66 mg, 57%) as a colorless oil. 1H-NMR (300 MHz, CDCl3, δ ppm): 7.94 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 8.1 Hz, 2H), 4.27 (t, J = 6.1 Hz, 2H), 4.12 (t, J = 6.1 Hz, 2H), 2.56 (s, 3H), 2.13–2.17 (m, 2H), 2.06 (s, 3H); 13C-NMR (75 MHz, CDCl3, δ ppm): 196.8, 171.0, 162.7, 130.6, 130.4, 114.1, 64.6, 61.0, 28.4, 26.3, 20.9; MS (ESI): m/z = 235.1 [M + H]+; Rf = 0.3 (DCM:MeOH 100:1).
3-(4-Cyanophenoxy)propyl acetate (3af). Compound 3af was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (86 mg, 79%) as a colorless oil. 1H-NMR (300 MHz, CDCl3, δ ppm): 7.58 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H), 4.26 (t, J = 6.1 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H), 2.07–2.18 (m, 2H), 2.04 (s, 3H); 13C-NMR (75 MHz, CDCl3, δ ppm): 161.5, 150.4, 133.4, 118.6, 114.6, 103.5, 64.2, 60.4, 27.8, 20.4; HRMS (ESI): m/z calcd. for C12H14NO4: 220.0968, found: 220.0972 [M + H]+; Rf = 0.3 (DCM:MeOH 100:1).
3-([1,1′-Biphenyl]-4-yloxy)propyl acetate (3ag). Compound 3ag (CAS: 1417800-59-9) was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (94 mg, 70%) as a light yellow solid. 1H-NMR (300 MHz, CDCl3, δ ppm): 7.58 (d, J = 8.2 Hz, 2H), 7.47 (t, J = 6.2 Hz, 2H), 7.34–7.41 (m, 3H), 7.10 (t, J = 8.2 Hz, 1H), 7.05 (t, J = 8.2 Hz, 1H), 4.22 (t, J = 6.1 Hz, 2H), 4.09 (t, J = 6.1 Hz, 2H), 2.09–2.13 (m, 2H), 2.05 (s, 3H); 13C-NMR (75 MHz, CDCl3, δ ppm): 170.5, 155.1, 137.9, 130.5, 129.0, 128.1, 127.4, 126.4, 120.7, 112.1, 64.3, 60.8, 28.1, 20.4; MS (ESI): m/z = 293.2 [M + Na]+; Rf = 0.5 (DCM:MeOH 100:1).
3-(Naphthalen-2-yloxy)propyl acetate (3ah). Compound 3ah (CAS: 1174495-88-5) was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (83 mg, 68%) as a yellow solid. 1H-NMR (300 MHz, CDCl3, δ ppm): 7.78–7.84 (m, 3H), 7.51 (t, J = 6.2 Hz, 1H), 7.40 (t, J = 6.2 Hz, 1H), 7.18–7.23 (m, 2H), 4.36 (t, J = 6.1 Hz, 2H), 4.17 (t, J = 6.1 Hz, 2H), 2.17–2.25 (m, 2H), 2.12 (s, 3H); 13C-NMR (75 MHz, CDCl3, δ ppm): 170.6, 156.3, 134.1, 129.0, 128.5, 127.2, 126.3, 125.9, 123.2, 118.4, 106.1, 63.8, 60.92, 28.1, 20.5; MS (ESI): m/z = 243.1 [M − H]−; Rf = 0.6 (DCM:MeOH 100:1).
3-(4-Chlorophenoxy)propyl benzoate (3ai). Compound 3ai was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (71 mg, 49%) as a light yellow solid. 1H-NMR (300 MHz, CDCl3, δ ppm): 8.08 (d, J = 8.2 Hz, 2H), 7.58 (t, J = 6.2 Hz, 1H), 7.46 (t, J = 6.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H), 4.55 (t, J = 6.1 Hz, 2H), 4.11 (t, J = 6.1 Hz, 2H), 2.23–2.31 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 165.9, 156.9, 132.5, 129.6, 129.0, 128.8, 127.9, 125.1, 115.2, 64.3, 61.2, 28.2; HRMS (ESI): m/z calcd. for C16H16ClO3: 291.0782, found: 291.0779 [M + H]+; Rf = 0.3 (DCM:MeOH 100:1).
3-(4-Formylphenoxy)propyl benzoate (3aj). Compound 3aj (CAS: 864845-56-7) was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 50:1) to provide the pure compound (67 mg, 47%) as a yellow solid. 1H-NMR (300 MHz, CDCl3, δ ppm): 9.88 (s, 1H, -CHO), 8.04 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.57 (t, J = 6.2 Hz, 1H), 7.42 (t, J = 8.2 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H), 4.54 (t, J = 6.1 Hz, 2H), 4.22 (t, J = 6.1 Hz, 2H), 2.26–2.33 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 190.3, 159.2, 132.5, 131.5, 129.0, 127.9, 114.2, 64.4, 61.0, 28.1; MS (ESI): m/z = 283.1 [M − H]−; Rf = 0.2 (DCM:MeOH 50:1).
3-(4-Cyanophenoxy)propyl benzoate (3ak). Compound 3ak was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (100 mg, 71%) as yellow solids. 1H-NMR (300 MHz, CDCl3, δ ppm): 8.07 (d, J = 8.6 Hz, 2H), 7.61 (t, J = 6.2 Hz, 1H), 7.46 (t, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H), 4.55 (t, J = 6.1 Hz, 2H), 4.11 (t, J = 6.1 Hz, 2H), 2.23–2.32 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 165.8, 161.5, 133.4, 132.5, 129.5, 129.0, 127.9, 118.7, 114.7, 103.4, 64.4, 61.0, 28.0; HRMS (ESI): m/z calcd. for C17H16NO3: 282.1125, found: 282.1129 [M + H]+; Rf = 0.6 (DCM:MeOH 50:1).
3-(Naphthalen-2-yloxy)propyl benzoate (3al). Compound 3al was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (99 mg, 65%) as yellow solids. 1H-NMR (300 MHz, DMSO-d6, δ ppm): 1H-NMR (300 MHz, CDCl3, δ ppm): 8.05 (d, J = 8.6 Hz, 2H), 7.78–7.85 (m, 3H), 7.60 (t, J = 6.2 Hz, 1H), 7.51 (t, J = 6.2 Hz, 1H), 7.37 (t, J = 6.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 4.62 (t, J = 6.1 Hz, 2H), 4.29 (t, J = 6.1 Hz, 2H), 2.31–2.40 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 166.1, 162.4, 133.9, 131.7, 129.1, 128.2, 127.6, 127.1, 126.8, 126.2, 123.6, 122.7, 118.9, 113.2, 106.3, 63.8, 61.4, 27.9; HRMS (ESI): m/z calcd. for C20H19O3: 307.1329, found: 307.1335 [M + H]+; Rf = 0.4 (DCM:MeOH 100:1).
3-(Naphthalen-2-yloxy)propyl 4-methoxybenzoate (3am). Compound 3am was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (114 mg, 68%) as yellow solids. 1H-NMR (300 MHz, CDCl3, δ ppm): 8.07 (d, J = 8.6 Hz, 2H), 7.76–7.83 (m, 3H), 7.49 (t, J = 6.2 Hz, 1H), 7.39 (t, J = 6.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 8.2 Hz, 2H), 4.60 (t, J = 6.1 Hz, 2H), 4.27 (t, J = 6.1 Hz, 2H), 3.86 (s, 3H, -OCH3), 2.36–2.42 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 165.8, 162.9, 156.3, 134.1, 131.2, 129.0, 128.5, 127.2, 126.3, 125.9, 123.2, 122.1, 118.5, 113.2, 106.1, 64.0, 61.1, 54.9, 28.3; HRMS (ESI): m/z calcd. for C21H21O4: 337.1434, found: 337.1431 [M + H]+; Rf = 0.3 (DCM:MeOH 100:1).
3-(Naphthalen-2-yloxy)propyl 4-nitrobenzoate (3an). Compound 3an was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 50:1) to provide the pure compound (108 mg, 62%) as yellow solids. 1H-NMR (300 MHz, CDCl3, δ ppm): 8.28 (d, J = 8.6 Hz, 2H), 8.21 (d, J = 8.6 Hz, 2H), 7.72–7.80 (m, 3H), 7.46 (t, J = 6.2 Hz, 1H), 7.37 (t, J = 6.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 2H), 4.66 (t, J = 6.1 Hz, 2H), 4.28 (t, J = 6.1 Hz, 2H), 2.36–2.42 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 164.1, 156.1, 149.9, 133.9, 130.5, 130.2, 129.0, 128.5, 127.1, 126.2, 125.9, 123.2, 123.0, 118.2, 106.0, 63.7, 62.4, 28.1; HRMS (ESI): m/z calcd. for C20H18NO5: 352.1179, found: 352.1175 [M + H]+; Rf = 0.2 (DCM:MeOH 100:1).
3-(4-Formylphenoxy)propyl 2-(2-chlorophenyl)acetate (3ao). Compound 3ao was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 50:1) to provide the pure compound (74 mg, 45%) as yellow solids. 1H-NMR (300 MHz, CDCl3, δ ppm): 9.87 (s, 2H, -CHO), 7.83 (d, J = 8.6 Hz, 2H), 7.35 (t, J = 6.2 Hz, 1H), 7.26–7.29 (m, 1H), 7.19–7.23 (m, 2H), 6.96 (d, J = 8.2 Hz, 2H), 4.33 (t, J = 6.1 Hz, 2H), 4.06 (t, J = 6.1 Hz, 2H), 3.78 (s, 2H), 2.12–2.16 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 190.2, 169.9, 163.2, 131.8, 131.4, 130.9, 129.5, 129.4, 128.9, 128.2, 126.4, 114.2, 64.0, 60.9, 38.7, 27.8; HRMS (ESI): m/z calcd. for C18H18ClO4: 333.0888, found: 333.0892 [M + H]+; Rf = 0.4 (DCM:MeOH 50:1).
3-(4-Cyanophenoxy)propyl (E)-3-(4-chlorophenyl)acrylate (3ap). Compound 3ap was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 40:1) to provide the pure compound (71 mg, 42%) as yellow solids. 1H-NMR (300 MHz, CDCl3, δ ppm): 7.63 (d, J = 15.6 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 8.1 Hz, 2H), 6.39 (d, J = 15.6 Hz, 1H), 4.40 (t, J = 6.1 Hz, 2H), 4.13 (t, J = 6.1 Hz, 2H), 2.17–2.6 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 166.5, 162.0, 143.6, 136.2, 133.9, 132.7, 129.2, 129.1, 119.2, 118.3, 115.1, 104.0, 64.8, 61.3, 28.4; HRMS (ESI): m/z calcd. for C19H17ClNO3: 342.0891, found: 342.0896 [M + H]+; Rf = 0.3 (DCM:MeOH 50:1).
3-(Naphthalen-2-yloxy)propyl cinnamate (3aq). Compound 3aq was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 50:1) to provide the pure compound (84 mg, 51%) as yellow solids. 1H-NMR (300 MHz, DMSO-d6, δ ppm): 1H-NMR (300 MHz, CDCl3, δ ppm): 7.74–7.85 (m, 4H), 7.53–7.59 (m, 2H), 7.49 (t, J = 6.2 Hz, 1H), 7.36–7.47 (m, 4H), 7.20–7.24 (m, 2H), 6.52 (d, J = 15.6 Hz, 1H), 4.53 (t, J = 6.1 Hz, 2H), 4.27 (t, J = 6.1 Hz, 2H), 2.27–2.37 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 166.5, 156.3, 144.5, 134.1, 133.8, 129.8, 128.9, 128.4, 127.6, 127.3, 127.2, 126.3, 125.9, 123.2, 118.4, 117.5, 106.1, 63.9, 61.0, 28.3; HRMS (ESI): m/z calcd. for C22H21O3: 333.1485, found: 333.1487 [M + H]+; Rf = 0.4 (DCM:MeOH 50:1).

3.3. 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 Cs2CO3 (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 Na2SO4, 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.
2-(4-Formylphenoxy)ethyl acetate (3ar). Compound 3ar (CAS: 151270-72-3) was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (76 mg, 73%) as a colorless oil. 1H-NMR (300 MHz, CDCl3, δ ppm): 9.84 (s, 1H, -CHO), 7.79 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 4.41 (t, J = 6.1 Hz, 2H), 4.22 (t, J = 6.1 Hz, 2H), 2.06 (s, 3H); 13C-NMR (75 MHz, CDCl3, δ ppm): 170.2, 162.8, 131.3, 129.6, 121.8, 114.2, 65.6, 61.8, 20.2; MS (ESI): m/z = 207.1 [M − H]−; Rf = 0.3 (DCM:MeOH 50:1).
2-(4-Cyanophenoxy)ethyl acetate (3as). Compound 3as (CAS: 150195-05-4) was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (79 mg, 77%) as a colorless oil. 1H-NMR (300 MHz, CDCl3, δ ppm): 7.56 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 4.41 (t, J = 6.1 Hz, 2H), 4.20 (t, J = 6.1 Hz, 2H), 2.07 (s, 3H); 13C-NMR (75 MHz, CDCl3, δ ppm): 170.3, 161.2, 133.4, 118.5, 114.7, 103.7, 65.6, 61.7, 20.3; MS (ESI): m/z = 204.1 [M − H]−; Rf = 0.3 (DCM:MeOH 100:1).
2-(4-Formylphenoxy)ethyl benzoate (3at). Compound 3at was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (94 mg, 70%) as a colorless oil. 1H-NMR (300 MHz, CDCl3, δ ppm): 9.91 (s, 1H, -CHO), 8.07 (d, J = 8.1 Hz, 2H), 7.87 (d, J = 8.1 Hz, 2H), 7.59 (t, J = 8.1 Hz, 1H), 7.43–7.48 (m, 2H), 7.07 (d, J = 8.1 Hz, 2H), 4.72 (t, J = 6.1 Hz, 2H), 4.41 (t, J = 6.1 Hz, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 165.9, 163.0, 132.7, 131.9, 131.5, 129.8, 129.2, 127.9, 115.8, 114.3, 65.7, 62.4; HRMS (ESI): m/z calcd. for C16H15O4: 271.0965, found: 271.0971 [M + H]+; Rf = 0.2 (DCM:MeOH 50:1).
2-(Naphthalen-1-yloxy)ethyl 4-methoxybenzoate (3au). Compound 3au was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (104 mg, 65%) as light yellow solids. 1H-NMR (300 MHz, CDCl3, δ ppm): 8.10 (d, J = 8.1 Hz, 2H), 7.77–7.84 (m, 3H), 7.51 (t, J = 8.1 Hz, 1H), 7.40 (t, J = 8.1 Hz, 1H), 7.25 (m, 1H), 6.93 (d, J = 8.1 Hz, 2H), 4.75 (t, J = 6.1 Hz, 2H), 4.42 (t, J = 6.1 Hz, 2H), 3.85 (s, 3H, -OCH3); 13C-NMR (75 MHz, CDCl3, δ ppm): 166.3, 163.5, 156.6, 134.5, 131.8, 129.6, 129.1, 127.7, 126.8, 126.5, 123.9, 122.3, 118.9, 113.7, 106.9, 66.1, 63.2, 55.4; HRMS (ESI): m/z calcd. for C20H19O4: 323.1278, found: 323.1273 [M + H]+; Rf = 0.4 (DCM:MeOH 50:1).
4-(Naphthalen-1-yloxy)butyl 4-methoxybenzoate (3av). Compound 3av was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (89 mg, 51%) as light yellow solids. 1H-NMR (300 MHz, CDCl3, δ ppm): 8.02 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.46 (t, J = 8.1 Hz, 1H), 7.36 (t, J = 8.1 Hz, 1H), 7.18 (m, 1H), 6.91 (d, J = 8.2 Hz, 2H), 4.43 (t, J = 6.1 Hz, 2H), 4.18 (t, J = 6.1 Hz, 2H), 3.86 (s, 3H, -OCH3), 2.03–2.05 (m, 4H); 13C-NMR (75 MHz, CDCl3, δ ppm): 165.9, 162.8, 156.3, 147.0, 134.0, 131.0, 128.9, 127.1, 126.2, 125.8, 123.0, 122.2, 118.4, 113.0, 106.1, 66.8, 63.9, 54.9, 25.5, 25.1; HRMS (ESI): m/z calcd. for C22H23O4: 351.1591, found: 351.1587 [M + H]+; Rf = 0.4 (DCM:MeOH 50:1).
4-(4-Chlorophenoxy)butyl acetate (3aw). Compound 3aw was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (65 mg, 54%) as a colorless oil. 1H-NMR (300 MHz, CDCl3, δ ppm): 7.23 (d, J = 8.2 Hz, 2H), 6.82 (d, J = 8.2 Hz, 2H), 4.15 (t, J = 6.1 Hz, 2H), 3.95 (t, J = 6.1 Hz, 2H), 2.07 (s, 3H), 1.82–1.86 (m, 4H); 13C-NMR (75 MHz, CDCl3, δ ppm): 157.0, 128.7, 124.9, 116.1, 115.2, 67.0, 63.6, 25.2, 24.8, 20.4; HRMS (ESI): m/z calcd. for C12H16O3Cl: 243.0782, found: 243.0786 [M + H]+; Rf = 0.5 (DCM:MeOH 100:1).
5-(4-Cyanophenoxy)pentyl benzoate (3ax). Compound 3ax was prepared following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (60 mg, 39%) as a colorless oil. 1H-NMR (300 MHz, CDCl3, δ ppm): 8.05 (d, J = 8.2 Hz, 2H), 7.55–7.59 (m, 3H), 7.45 (t, J = 6.3 Hz, 1H), 6.94 (d, J = 8.2 Hz, 2H), 4.38 (t, J = 6.1 Hz, 2H), 4.04 (t, J = 6.1 Hz, 2H), 1.83–1.95 (m, 4H), 1.60–1.70 (m, 2H); 13C-NMR (75 MHz, CDCl3, δ ppm): 166.6, 162.2, 133.9, 132.9, 129.5, 128.3, 119.3, 115.1, 68.0, 64.6, 28.6, 28.4, 22.6; HRMS (ESI): m/z calcd. for C19H20O3N: 310.1438, found: 310.142 [M + H]+; Rf = 0.6 (DCM:MeOH 50:1).
((5-Hydroxy-4-oxo-2-phenyl-4H-chromene-6,7-diyl)bis(oxy))bis(propane-3,1-diyl) diacetate (3ay). Compound 3ay was prepared from 6,7-diacetyl baicalein following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 50:1) to provide the pure compound (110 mg, 47%) as yellow solids. 1H-NMR (300 MHz, CDCl3, δ ppm): 12.67 (s, 1H, -OH), 7.90 (d, J = 8.1 Hz, 2H), 7.51–7.60 (m, 3H), 6.69 (s, 1H), 6.57 (s, 1H), 4.37 (t, J = 6.1 Hz, 2H), 4.33 (t, J = 6.1 Hz, 2H), 4.18 (t, J = 6.1 Hz, 2H), 4.15 (t, J = 6.1 Hz, 2H), 2.21–2.30 (m, 2H), 2.13 (m, 2H), 2.10 (s, 3H), 2.08 (s, 3H); HRMS (ESI): m/z calcd. for C25H27O9: 471.1650, found: 471.1659 [M + H]+; Rf = 0.6 (DCM:MeOH 30:1).
2-((5,6-Dihydroxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)ethyl acetate (3az). Compound 3az was prepared from 7-acetyl baicalein following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 40:1) to provide the pure compound (76 mg, 43%) as yellow solids. 1H-NMR (300 MHz, DMSO-d6, δ ppm): 12.53 (s, 1H, -OH), 8.81 (s, 1H, -OH), 8.06–8.11 (m, 2H), 7.55–7.63 (m, 3H), 7.00 (s, 1H), 6.98 (s, 1H), 4.39 (t, J = 6.1 Hz, 2H), 4.35 (t, J = 6.1 Hz, 2H), 2.07 (s, 3H); 13C-NMR (75 MHz, DMSO-d6, δ ppm): 182.2, 170.3, 163.1, 153.2, 149.5, 146.2, 131.9, 130.7, 130.2, 129.0, 126.2, 105.4, 104.6, 92.1, 66.9, 62.2, 20.6; HRMS (ESI): m/z calcd. for C19H17O7: 357.0969, found: 357.0975 [M + H]+; Rf = 0.3 (DCM:MeOH 30:1).
3-((5-Hydroxy-8-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl)oxy)propyl acetate (3ba). Compound 3ba was prepared from 7-acetyl wogonin following the general procedure described above and purified by silica gel column chromatography (DCM:MeOH 50:1) to provide the pure compound (132 mg, 69%) as yellow solids. 1H-NMR (300 MHz, CDCl3, δ ppm): 12.56 (s, 1H, -OH), 7.95 (t, J = 6.1 Hz, 2H), 7.55 (m, 3H), 6.69 (s, 1H), 6.44 (s, 1H), 4.33 (t, J = 6.1 Hz, 2H), 4.19 (t, J = 6.1 Hz, 2H), 3.94 (s, 3H, -OCH3), 2.19–2.28 (m, 2H), 2.10 (s, 3H); 13C-NMR (75 MHz, CDCl3, δ ppm): 182.7, 178.0, 164.1, 163.9, 157.9, 1574, 157.3, 131.9, 131.2, 129.1, 126.3, 126.2, 105.3, 96.5, 65.5, 61.6, 60.9, 28.4, 20.9; HRMS (ESI): m/z calcd. for C21H21O7: 385.1282, found: 385.1278 [M + H]+; Rf = 0.3 (DCM:MeOH 50:1).

3.4. 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 K2CO3 (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 CH2Cl2 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 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). 1H-NMR (300 MHz, CDCl3, δ ppm): 7.94–8.01 (m, 3H), 7.69 (t, J = 6.1 Hz, 1H), 7.58 (t, J = 6.1 Hz, 1H), 7.49 (dd, J = 8.1 Hz, 1.8 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 5.85 (t, J = 6.2 Hz, 1H, -CH=C), 4.83 (d, J = 9.1 Hz, 2H, -CH2-), 2.06 (s, 3H, -CH3), 1.99 (s, 3H, -CH3); 13C-NMR (75 MHz, CDCl3, δ ppm): 156.7, 137.6, 134.4, 129.2, 127.4, 126.5, 126.1, 123.3, 119.6, 118.9, 115.2, 106.4, 64.4, 25.6, 17.9; MS (ESI): m/z = 213.1 [M + H]+; Rf = 0.7 (DCM:MeOH 100:1).
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 K2CO3 (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 CH2Cl2 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 by silica gel column chromatography with hexane/EtOAc (4:1 v/v) to afford the desired compound, 5 (CAS: 7598-29-0), as a slightly yellow oil (96 mg, 95% yield). 1H-NMR (300 MHz, CDCl3, δ ppm): 7.74–7.82 (m, 3H), 7.48 (t, J = 6.2 Hz, 1H), 7.38 (t, J = 6.2 Hz, 1H), 7.19–7.24 (m, 2H), 4.63 (br s, 1H, -OH), 4.22 (t, J = 6.1 Hz, 2H), 4.05 (t, J = 6.1 Hz, 2H), 2.16–2.19 (m, 2H); MS (ESI): m/z = 203.1 [M + H]+; Rf = 0.4 (DCM:MeOH 50:1).
Butyl 4-methoxybenzoate (10). Compound 10 (CAS: 6946-35-6) was prepared from 1v and 1-butanol (2f), following the above general procedure and purified by silica gel column chromatography (DCM:MeOH 100:1) to provide the pure compound (59 mg, 57%) as a light oil. 1H-NMR (300 MHz, CDCl3, δ ppm): 8.01 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 4.30 (t, J = 6.2 Hz, 2H), 3.85 (s, 3H, -OCH3), 1.74 (m, 2H), 1.49 (m, 2H), 0.98 (t, J = 6.2 Hz, 3H); 13C-NMR (75 MHz, CDCl3, δ ppm): 165.9, 162.7, 131.0, 122.4, 113.0, 64.0, 54.8, 30.3, 18.7, 13.2; MS (ESI): m/z = 209.1 [M + H]+; Rf = 0.8 (DCM:MeOH 100:1).
5-Hydroxy-8-methoxy-4-oxo-2-phenyl-4H-chromen-7-yl acetate (7-acetyl wogonin). 5-Acetyl wogonin (65 mg, 0.2 mmol) were loaded into a flask (25 mL). DMF (1.5 mL) and K2CO3 (82 mg, 0.6 mmol, 3.0 equiv) was added. 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 5 mL of CH2Cl2 and 5 mL of water were added. After separation of the CH2Cl2 layer from the water, the aqueous phase was extracted with CH2Cl2 (2 × 3 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 by silica gel column chromatography with hexane/EtOAc (5:1 v/v) to afford 7-acyl wogonin (CAS: 95480-80-1) as slightly yellow solids (56 mg, 86% yield). 1H-NMR (300 MHz, DMSO-d6, δ ppm): 12.49 (s, 1H, 5-OH), 7.99–8.02 (m, 2H, H-2′, H-6′), 7.63–7.69 (m, 3H, H-3′, H-4′, H-5′), 6.73 (s, 1H, H-3), 6.38 (s, 1H, H-6), 3.81 (s, 3H, 8-OCH3), 2.19 (s, 3H, -CH3); MS (ESI): m/z = 325.1 [M − H]−; Rf = 0.3 (DCM:MeOH 100:1).

4. 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 (SN2) 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.

Supplementary Materials

The following are available online, characterization data: HRMS, 1H-NMR, and 13C-NMR spectra of all new compounds.

Author Contributions

F.F. and W.Q. conceived and designed the experiments; X.J. and J.Z. performed the experiments; J.X. analyzed the data X.J., Y.Z., and H.S. wrote the paper.

Funding

This research was funded by the National Natural Science Foundation of China (Nos. 81502950 and 81703382) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Acknowledgments

We are grateful to Qi Li for the touch of the manuscript. Special thanks should go to editors and reviewers who have put considerable time and effort into their kindly comments on the draft.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Mesganaw, T.; Garg, N.K. Ni- and Fe-catalyzed cross-coupling reactions of phenol derivatives. Org. Process Res. Dev. 2013, 17, 29–39. [Google Scholar] [CrossRef]
  2. Correa, A.; Cornella, J.; Martin, R. Nickel-catalyzed decarbonylative C-H coupling reactions: A strategy for preparing bis(heteroaryl) backbones. Angew. Chem. Int. Ed. 2013, 52, 1878–1880. [Google Scholar] [CrossRef] [PubMed]
  3. Tobisu, M.; Chatani, N. Catalytic transformations involving the activation of sp2 carbon–oxygen bonds. Top. Organomet. Chem. 2012, 44, 35–53. [Google Scholar]
  4. Hanley, P.S.; Clark, T.P.; Krasovskiy, A.L.; Ober, M.S.; O’Brien, J.P.; Staton, T.S. Palladium- and Nickel-catalyzed amination of aryl fluorosulfonates. ACS Catal. 2016, 6, 3515–3519. [Google Scholar] [CrossRef]
  5. Chen, Q.; Yu, H.; Xu, Z.; Lin, L.; Jiang, X.; Wang, R. Development and application of O-(Trimethylsilyl) aryl fluorosulfates for the synthesis of arynes. J. Org. Chem. 2015, 80, 6890–6896. [Google Scholar] [CrossRef] [PubMed]
  6. Ackermann, L.; Sandmann, R.; Song, W. Palladium-and nickel-catalyzed aminations of aryl imidazolylsulfonates and sulfamates. Org. Lett. 2011, 13, 1784–1786. [Google Scholar] [CrossRef] [PubMed]
  7. Ramgren, S.D.; Silberstein, A.L.; Yang, Y.; Garg, N.K. Nickel-catalyzed amination of aryl sulfamates. Angew. Chem. Int. Ed. 2011, 50, 2171–2173. [Google Scholar] [CrossRef] [PubMed]
  8. Hie, L.; Ramgren, S.D.; Mesganaw, T.; Garg, N.K. Nickel-catalyzed amination of aryl sulfamates and carbamates using an air-stable precatalyst. Org. Lett. 2012, 14, 4182–4185. [Google Scholar] [CrossRef] [PubMed]
  9. Roy, A.H.; Hartwig, J.F. Oxidative addition of aryl tosylates to palladium (0) and coupling of unactivated aryl tosylates at room temperature. J. Am. Chem. Soc. 2003, 125, 8704–8705. [Google Scholar] [CrossRef] [PubMed]
  10. Ogata, T.; Hartwig, J.F. Palladium-catalyzed amination of aryl and heteroaryl tosylates at room temperature. J. Am. Chem. Soc. 2008, 130, 13848–13849. [Google Scholar] [CrossRef] [PubMed]
  11. Xu, G.; Wang, Y.G. Microwave-assisted amination from aryl triflates without base and catalyst. Org. Lett. 2004, 6, 985–987. [Google Scholar] [CrossRef] [PubMed]
  12. Vila, C.; Hornillos, V.; Giannerini, M.; Fañanás-Mastral, M.; Feringa, B.L. Palladium-catalysed direct cross-coupling of organolithium reagents with aryl and vinyl triflates. Chem. Eur. J. 2014, 20, 13078–13083. [Google Scholar] [CrossRef] [PubMed]
  13. Leowanawat, P.; Zhang, N.; Percec, V. Nickel catalyzed cross-coupling of aryl C–O based electrophiles with aryl neopentylglycolboronates. J. Org. Chem. 2012, 77, 1018–1025. [Google Scholar] [CrossRef] [PubMed]
  14. Niculescu-Duvaz, I.; Scanlon, I.; Niculescu-Duvaz, D.; Friedlos, F.; Martin, J.; Marais, R.; Springer, C.J. Significant differences in biological parameters between prodrugs cleavable by carboxypeptidase G2 that generate 3,5-difluoro-phenol and-aniline nitrogen mustards in gene-directed enzyme prodrug therapy systems. J. Med. Chem. 2004, 47, 2651–2658. [Google Scholar] [CrossRef] [PubMed]
  15. Abraham, S.; Guo, F.; Li, L.S.; Rader, C.; Liu, C.; Barbas, C.F.; Sinha, S.C.P. Synthesis of the next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation. Proc. Natl. Acad. Sci. USA 2007, 104, 5584–5589. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Quasdorf, K.W.; Antoft-Finch, A.; Liu, P.; Silberstein, A.L.; Komaromi, A.; Blackburn, T.; Ramgren, S.D.; Houk, K.N.; Snieckus, V.; Garg, N.K. Suzuki–Miyaura cross-coupling of aryl carbamates and sulfamates, experimental and computational studies. J. Am. Chem. Soc. 2011, 133, 6352–6363. [Google Scholar] [CrossRef] [PubMed]
  17. Ohtsuki, A.; Yanagisawa, K.; Furukawa, T.; Tobisu, M.; Chatani, N. Nickel/N-Heterocyclic carbene-catalyzed Suzuki–Miyaura type cross-coupling of aryl carbamates. J. Org. Chem. 2016, 81, 9409–9414. [Google Scholar] [CrossRef] [PubMed]
  18. Guo, L.; Hsiao, C.C.; Yue, H.; Liu, X.; Rueping, M. Nickel-catalyzed csp2–csp3 cross-coupling via C–O bond activation. ACS Catal. 2016, 6, 4438–4442. [Google Scholar] [CrossRef]
  19. Zhao, Y.L.; Li, Y.; Li, Y.; Gao, L.X.; Han, F.S. Aryl phosphoramides: Useful electrophiles for suzuki–miyaura coupling catalyzed by a NiCl2/dppp system (dppp = 1,3-bis(diphenylphosphino) propane). Chem. Eur. J. 2010, 16, 4991–4994. [Google Scholar] [CrossRef] [PubMed]
  20. Li, S.M.; Huang, J.; Chen, G.J.; Han, F.S. PdCl2 (dppf)-catalyzed in situ coupling of 2-hydroxypyridines with aryl boronic acids mediated by PyBroP and the one-pot chemo-and regioselective construction of two distinct aryl–aryl bonds. Chem. Commun. 2011, 47, 12840–12842. [Google Scholar] [CrossRef] [PubMed]
  21. Chen, H.; Huang, Z.; Hu, X.; Tang, G.; Xu, P.; Zhao, Y.; Cheng, C.H. Nickel-catalyzed cross-coupling of aryl phosphates with arylboronic acids. J. Org. Chem. 2011, 76, 2338–2344. [Google Scholar] [CrossRef] [PubMed]
  22. Quasdorf, K.W.; Tian, X.; Garg, N.K. Cross-coupling reactions of aryl pivalates with boronic acids. J. Am. Chem. Soc. 2008, 130, 14422–14423. [Google Scholar] [CrossRef] [PubMed]
  23. Cornella, J.; Zarate, C.; Martin, R. Metal-catalyzed activation of ethers via C–O bond cleavage; a new strategy for molecular diversity. Chem. Soc. Rev. 2014, 43, 8081–8097. [Google Scholar] [CrossRef] [PubMed]
  24. Li, B.J.; Yu, D.G.; Sun, C.L.; Shi, Z. Activation of “inert” alkenyl/aryl C–O bond and its application in cross-coupling reactions. Chem. Eur. J. 2011, 17, 1728–1759. [Google Scholar] [CrossRef] [PubMed]
  25. Rosen, B.M.; Quasdorf, K.W.; Wilson, D.A.; Zhang, N.; Resmerita, A.M.; Garg, N.K.; Percec, V. Nickel-catalyzed cross-couplings involving carbon-oxygen bonds. Chem. Rev. 2010, 111, 1346–1416. [Google Scholar] [CrossRef] [PubMed]
  26. Tobisu, M.; Chatani, N. Cross-couplings using aryl ethers via C–O bond activation enabled by Nickel catalysts. Acc. Chem. Res. 2015, 48, 1717–1726. [Google Scholar] [CrossRef] [PubMed]
  27. Selvarani, S.; Rajakumar, P. Synthesis and antibacterial activity of some novel piperazinophanes with an intraannular ester functionality. New J. Chem. 2016, 40, 9494–9499. [Google Scholar] [CrossRef]
  28. Wang, L.; Li, J.; Dai, W.; Lv, Y.; Zhang, Y.; Gao, S. Facile and efficient gold-catalyzed aerobic oxidative esterification of activated alcohols. Green Chem. 2014, 16, 2164–2173. [Google Scholar] [CrossRef]
  29. Li, Y.; Wang, L.; Yan, R.; Han, J.; Zhang, S. Gold nanoparticles supported on Ce-Zr oxides for the oxidative esterification of aldehydes to esters. Catal. Sci. Technol. 2015, 5, 3682–3692. [Google Scholar] [CrossRef]
  30. Ghosh, K.; Iqubal, M.A.; Molla, R.A.; Mishra, A.; Islam, S.M. Direct oxidative esterification of alcohols and hydration of nitriles catalyzed by a reusable silver nanoparticle grafted onto mesoporous polymelamine formaldehyde (AgNPs@mPMF). Catal. Sci. Technol. 2015, 5, 1606–1622. [Google Scholar] [CrossRef]
  31. Greig, I.R.; Macauley, M.S.; Williams, I.H.; Vocadlo, D.J. Probing synergy between two catalytic strategies in the glycoside hydrolase O-GlcNAcase using multiple linear free energy relationships. J. Am. Chem. Soc. 2009, 131, 13415–13422. [Google Scholar] [CrossRef] [PubMed]
  32. Jiang, X.Y.; Li, X.C.; Liu, W.Y.; Xu, Y.H.; Feng, F.; Qu, W. An efficient, scalable approach to hydrolyze flavonoid glucuronides via activation of glycoside bond. Tetrahedron 2017, 73, 1895–1903. [Google Scholar] [CrossRef]
  33. Shridhar, D.R.; Sastry, C.V.R.; Vaidya, N.K.; Reddi, G.S.; Thapar, G.S. Antimicrobial agents: Synthesis and antimicrobial activity of new aryloxyalkyl esters of p-hydroxybenzoic acid. J. Pharm. Sci. 1976, 65, 1074–1078. [Google Scholar] [CrossRef] [PubMed]
  34. Jin, H.; Zhang, W.; Wang, D.; Chu, Z.; Shen, Z.; Zou, D.; Zhou, Q. Dendron-Jacketed electrophosphorescent copolymers: Improved efficiency and tunable emission color by partial energy transfer. Macromolecules 2011, 44, 9556–9564. [Google Scholar] [CrossRef]
  35. Kawatsuki, N.; Tsutsumi, R.; Takatsuka, H.; Sakai, T. Influence of alkylene spacer length on thermal enhancement of photoinduced optical anisotropy in photo-cross-linkable liquid crystalline polymeric films and yheir composites with non-liquid-crystalline monomers. Macromolecules 2007, 40, 6355–6360. [Google Scholar] [CrossRef]
  36. Quici, S.; Cavazzini, M.; Raffo, M.C.; Armelao, L.; Bottaro, G.; Accorsi, G.; Barigelletti, F. Highly homogeneous, transparent and luminescent SiO2 glassy layers containing a covalently bound tetraazacyclododecane-triacetic acid-Eu(III)-acetophenone complex. J. Mater. Chem. 2006, 16, 741–747. [Google Scholar] [CrossRef]
  37. Lafuente, L.; Díaz, G.; Bravo, R.; Ponzinibbio, A. Efficient and selective N-; S- and O-acetylation in TEAA ionic liquid as green solvent. Applications in synthetic carbohydrate chemistry. Lett. Org. Chem. 2016, 13, 195–200. [Google Scholar] [CrossRef]
  38. Roche, C.P.; Brei, M.R.; Yang, B.; Storey, R.F. Direct chain end functionalization of living polyisobutylene using phenoxyalkyl (meth)acrylates. ACS Macro Lett. 2014, 3, 1230–1234. [Google Scholar] [CrossRef]
  39. Jeyakumar, K.; Chand, D.K. Copper perchlorate: Efficient acetylation catalyst under solvent free conditions. J. Mol. Catal. A Chem. 2006, 255, 275–282. [Google Scholar] [CrossRef]
Sample Availability: Samples of the compounds 3aa–3bb are available from the authors.
Molecules 23 01715 sch001 550
Scheme 1. The structures of C-O electrophiles and their subsequent conformation of C-C bonds, C-N bonds, and C-H bonds.
Scheme 1. The structures of C-O electrophiles and their subsequent conformation of C-C bonds, C-N bonds, and C-H bonds.
Molecules 23 01715 sch001
Molecules 23 01715 sch002 550
Scheme 2. The new method to synthesize aryloxyalkyl ester.
Scheme 2. The new method to synthesize aryloxyalkyl ester.
Molecules 23 01715 sch002
Molecules 23 01715 sch003 550
Scheme 3. Scope of the reaction of phenol esters.
Scheme 3. Scope of the reaction of phenol esters.
Molecules 23 01715 sch003
Molecules 23 01715 sch004 550
Scheme 4. Scope of the reaction of halogenated alcohols and application to the synthesis of flavonoid derivatives.
Scheme 4. Scope of the reaction of halogenated alcohols and application to the synthesis of flavonoid derivatives.
Molecules 23 01715 sch004
Molecules 23 01715 sch005 550
Scheme 5. Control experiments to investigate the mechanism.
Scheme 5. Control experiments to investigate the mechanism.
Molecules 23 01715 sch005
Molecules 23 01715 sch006 550
Scheme 6. Proposed mechanism for the synthesis of aryloxyalkyl ester derivatives in the presence of potassium carbonate (A), or in the presence of NaH (B).
Scheme 6. Proposed mechanism for the synthesis of aryloxyalkyl ester derivatives in the presence of potassium carbonate (A), or in the presence of NaH (B).
Molecules 23 01715 sch006
Molecules 23 01715 sch007 550
Scheme 7. The acyl of 5-O-wogonin was transferred to the 7-position, forming 7-acetyl wogonin in the presence of potassium carbonate.
Scheme 7. The acyl of 5-O-wogonin was transferred to the 7-position, forming 7-acetyl wogonin in the presence of potassium carbonate.
Molecules 23 01715 sch007
Table
Table 1. Condition optimization for aryloxyalkyl esterification. a
Table 1. Condition optimization for aryloxyalkyl esterification. a
Molecules 23 01715 i001
EntryBaseEquivSolventTemp.Yield (%) b
1K2CO31.5acetone60 °C59
2K2CO31.5THF60 °C51
3K2CO31.5MeCN60 °C54
4K2CO31.5DMF80 °C65
5K2CO33DMF80 °C72
6-- c--DMF80 °CNR d
7KHCO33DMF80 °C13
8Cs2CO33DMF80 °C76
9NaH3DMF60 °C73
10NaOH1.5MeCN60 °CTrace
a Reaction conditions: Except where otherwise noted, all of the reactions were performed with 1a (0.5 mmol), 2a (0.525 mmol), and a base in the solvent (1.5 mL) for 6 h under an Ar atmosphere. b Yield of isolated product. c --: No base exists. d NR: No reaction. Thin layer chromatography (TLC) showed the presence of starting materials, 1a, and detected no new product.

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Jiang, X.; Zhou, J.; Zhou, Y.; Sun, H.; Xu, J.; Feng, F.; Qu, W. Convenient Method of Synthesizing Aryloxyalkyl Esters from Phenolic Esters Using Halogenated Alcohols. Molecules 2018, 23, 1715. https://doi.org/10.3390/molecules23071715

AMA Style

Jiang X, Zhou J, Zhou Y, Sun H, Xu J, Feng F, Qu W. Convenient Method of Synthesizing Aryloxyalkyl Esters from Phenolic Esters Using Halogenated Alcohols. Molecules. 2018; 23(7):1715. https://doi.org/10.3390/molecules23071715

Chicago/Turabian Style

Jiang, Xueyang, Junting Zhou, Yue Zhou, Haopeng Sun, Jian Xu, Feng Feng, and Wei Qu. 2018. "Convenient Method of Synthesizing Aryloxyalkyl Esters from Phenolic Esters Using Halogenated Alcohols" Molecules 23, no. 7: 1715. https://doi.org/10.3390/molecules23071715

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