Efficient and Rapid Solvent-Free Acetylation of Alcohols, Phenols, and Thiols Using Catalytic Amounts of Sodium Acetate Trihydrate

Mojtahedi, Mohammad M.; Samadian, Shamim

doi:https://doi.org/10.1155/2013/642479

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Research Article | Open Access

Volume 2013 | Article ID 642479 | https://doi.org/10.1155/2013/642479

Efficient and Rapid Solvent-Free Acetylation of Alcohols, Phenols, and Thiols Using Catalytic Amounts of Sodium Acetate Trihydrate

Mohammad M. Mojtahedi¹and Shamim Samadian¹

Academic Editor: Stojan Stavber

Received29 May 2013

Accepted21 Jul 2013

Published19 Aug 2013

Abstract

Under solvent-free conditions, different alcohols and phenols were efficiently acetylated at room temperature within short time periods by using acetic anhydride in the presence of catalytic quantities of sodium acetate trihydrate, which is a very inexpensive and mild reagent. Thiols were also shown to behave equally well under the same conditions. Chemoselective protection of less hindered alcohols in the presence of bulkier homologues and phenols in the presence of alcohols was achieved using competitive experiments.

1. Introduction

Protection of alcohols and phenols is one of the most common synthetic strategies utilized to mask hydroxyl functionalities during multistep synthetic procedures [1, 2]. In addition, O-acetylation procedures are widely employed for the protection and purification of various natural and synthetic products containing carbohydrate substructures [3–5]. Among various hydroxyl groups protecting moieties, acetyl is perhaps the most frequently used group due to the ease of introduction and its stability [6, 7]. In addition, the acetate products can be efficiently converted to their respective original alcohols using various mild procedures [8, 9]. Acetylation of alcohols is traditionally carried out in the presence of excessive amounts of acetic anhydride or acetyl chloride and an amine base [10]. More efficient alternative methods are developed in recent years using Lewis acids [11–16], solid supports [17–23], microwave irradiation [24–26], ultrasonic activation [27], solid protic acids [28–30], ionic liquids [31–33], and enzymes [34, 35]. However, still in many of these methods use of excessive acetic anhydride, application of toxic metal containing catalysts, and involvement of tedious work-up conditions are required.

In the framework of our studies to design ecofriendly synthetic procedures [36–39] and in continuation of our program to develop efficient procedures for functional groups protection [40–42], we recently reported an environmentally benign chemoselective process for spontaneous acetylation of various amines by acetic anhydride at room temperature by using no catalyst or additive [43]. However, under the conditions, thiols were acetylated in a much slower fashion and alcohols remained intact. This persuaded us to search for an alternative mild procedure under which alcohols and thiols could also be acetylated efficiently. As a result of our investigations, we hereby report a novel protocol for rapid and selective acetylation of alcohols, phenols, and thiols under solvent-free conditions by using only catalytic amounts of inexpensive sodium acetate trihydrate (NaOAc·3H₂O) (Scheme 1).

2. Results and Discussion

The isolated yields obtained for room-temperature acetylation of selected alcohols and phenols in the presence of acetic anhydride and NaOAc·3H₂O are given in Table 1. Experiments with several solvents showed that the best results would be obtained under solvent-free conditions. When a solvent-free 1.0 : 1.0 : 0.1 mixture of 1-butanol, acetic anhydride, and NaOAc·3H₂O was stirred at room temperature, complete formation of butyl acetate was observed within 20 minutes (entry 1). The ¹H NMR and GC spectra of the reaction mixture showed the presence of butyl acetate as the sole product of the reaction. The applicability of this method to other substrates was evaluated by using the same conditions for other primary (entries 2-3), propargylic (entry 4), allylic (entry 5), benzylic (entries 6–11), secondary (entries 12–16), and tertiary (entries 17-18) alcohols. In all cases, rapid formation of the respective acetates was observed in high yields within 10–70 minutes. Further generality of this procedure was demonstrated by convenient conversion of phenols with different stereoelectronic nature to their corresponding acetates (entries 19–23). The methodology was also applied for efficient protection of the chiral alcohols menthol (entry 24) and ethyl lactate (entry 25), while their chirality was maintained during the process. Interestingly, acetylsalicylic acid (aspirin) was easily prepared in high yields and purity by using the conditions (entry 26). This could be a very important result from an industrial point of view, since aspirin is normally produced under very strong acidic conditions [44, 45]. The development of the work in large-scale preparation of aspirin is under investigation.

We next decided to use this chemistry for the protection of thiols due to the importance of their masking [15, 47, 48] in synthesis [1, 2], biochemistry [49], and electrochemistry [50, 51]. Therefore, thiophenol, 4-chlorothiophenol, naphthalene-2-thiol, phenylmethanethiol, and furan-2-ylmethanethiol were conveniently acetylated in less than 1 h under the conditions similar to those employed for alcohols (Table 2).

As previously noticed [43], alcohols and phenols react with acetic anhydride considerably slower than amines and thiols. This phenomenon persuaded us to evaluate the feasibility of selective protection of hydroxyl groups in the presence of competent functionalities. The results shown in Table 3 clearly illustrate that primary alcohols are acetylated in the presence of secondary (entry 1) or tertiary (entry 2) alcohols with very high selectively. On the other hand, competition between secondary and tertiary (entry 3) or primary and benzylic (entry 4) hydroxyls results in preferential protection of secondary or benzylic alcohols, respectively. These results correlate with relative acidic strength of the alcohols and are verified by preferential protection of phenol in the presence of benzyl alcohol (entry 5) and thiophenol in the presence of phenol (entry 6). However, it seems that acidity is not a determining function when aromatic amines are involved. As a result, aniline is dominantly protected when it competes with phenol (entry 7) or with thiophenol (entry 8). Similarly, intramolecular competition between NH₂ and OH groups in 4-aminophenol led to exclusive formation of N-(4-hydroxyphenyl) acetamide (paracetamol) (entry 9), a widely used over-the-counter analgesic drug [52]. This difference in activity might be attributed to higher nucleophilicity of the amine and spontaneous precipitation of the amide product. The difference in nucleophilicity is enhanced in the case of 4-aminophenol (entry 9), where the amine group is further activated by electron donating effects of the OH moiety through resonance.

In conclusion, we disclosed a very inexpensive and straightforward procedure for catalytic conversion of various alcohols and phenols to their respective acetyl products in high yields and short time periods. High chemoselectivity and generality of the procedure, lack of formation of side products, easy workup, use of minimum quantities of Ac₂O, and the environmental safety of the reactions are among the advantages of the present methodology. Application of the method in protection of carbohydrates is under investigation. To further highlight the efficiency of the present procedure, Table 4 is provided to compare the results of NaOAc catalyzed acetylation of benzyl alcohol with some other recently developed methods. It can easily be concluded from this comparison that the present reaction does not require high temperature treatment or use of complicated reagents to proceed. In addition, the reaction takes place rapidly by using no solvent.

3. Experimental

3.1. General Remarks

IR spectra were recorded using KBr disks on a Bruker Vector-22 infrared spectrometer. ¹H NMR spectra were obtained on an FT-NMR Bruker Ultra Shield (500 MHz) or Bruker AC 80 MHz instrument as CDCl₃ solutions using TMS as the internal standard reference. All chemicals were purchased from commercial sources.

3.2. General Procedure

A solvent-free mixture of an alcohol or thiol (1.0 mmol), acetic anhydride (1.1 mmol), and NaOAc·3H₂O (10 mol%) was stirred at room temperature for appropriate length of time, as indicated in Tables 1 and 2 until TLC and/or GC showed completion of the reaction. The mixture was diluted by diethyl ether (10 mL) and washed with saturated solution of NaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using EtOAc/hexane eluant, if necessary. All products were known and their identities were confirmed by comparing their spectral data with those available in the literature.

Acknowledgment

The Analytical Department at the Chemistry and Chemical Engineering Research Center of Iran is gratefully acknowledged for conducting the GC experiments.

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Copyright © 2013 Mohammad M. Mojtahedi and Shamim Samadian. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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