Acetylation of Phenols , Anilines , and Thiols Using Silica Sulfuric Acid under Solvent-Free Conditions

e protection of hydroxyl groups of alcohols and phenols is oen necessary during the course of various transformations in a synthetic sequence, especially in the construction of polyfunctionalmolecules such as nucleosides, carbohydrates, steroids, and natural products. A variety of procedures are routinely performed for the preparation of acetyl derivatives, including homogeneous or heterogeneous catalysts. Protection reactions have to proceed rapidly, readily, quantitatively, and keeping costs to a minimum. Typically, the acetylation of hydroxyl groups is performed with an excess of Ac2O under basic or acidic catalysis; in some cases, acetyl halides have been used [1, 2]. Several methods have been developed for preparation of acetate from the corresponding phenol or thiol using various metal salts, such as CoCl2 [3], ZnCl2 [4], RuCl3 [5], TiCl4AgClO4 [6], LiClO4 [7], Mg(ClO4)2 [8], Zn(ClO4)2⋅6H2O [9], and some tri�ates such as Sc(OTf)3 [10], Me3SiOTf [11], In(OTf)3 [12], Cu(OTf)2 [13, 14], Ce(OTf)3 [15], and Bi(OTf)3 [16]. e Cp2Sm(thf)2 [17], tetrabutyl ammonium salt [18], and vinyl carboxylate [19] have proved to be the best catalysts for the acylation of amines with esters. However, quite a few of the reported methods have limitations mainly in respect of stability, cost, availability, load, and reusability of the catalyst or in terms of yields and �ammability or risk of explosion of the reagents. us, there is still a demand to develop new and mild methods for the acetylation in the presence of inexpensive and bench top reagents. In continuation to our environmentally benign synthesis and synthesis of nitrogen-containing compounds [20–27], we intend to report a mild, clean, simple, and efficient method for the acetylation of phenols, amines, and thiols with Ac2O in the presence of silica sulfuric acid (SSA) [28] as a heterogeneous catalyst under solvent-free conditions [29–33] at room temperature (Scheme 1).


Introduction
e protection of hydroxyl groups of alcohols and phenols is oen necessary during the course of various transformations in a synthetic sequence, especially in the construction of polyfunctional molecules such as nucleosides, carbohydrates, steroids, and natural products.A variety of procedures are routinely performed for the preparation of acetyl derivatives, including homogeneous or heterogeneous catalysts.Protection reactions have to proceed rapidly, readily, quantitatively, and keeping costs to a minimum.Typically, the acetylation of hydroxyl groups is performed with an excess of Ac 2 O under basic or acidic catalysis; in some cases, acetyl halides have been used [1,2].
However, quite a few of the reported methods have limitations mainly in respect of stability, cost, availability, load, and reusability of the catalyst or in terms of yields and �ammability or risk of explosion of the reagents.us, there is still a demand to develop new and mild methods for the acetylation in the presence of inexpensive and bench top reagents.

General Experimental Procedure.
A mixture of substrate (phenol, amine, thiol, or thiophenol) (1.0 mM), Ac 2 O (2.0 mM), and SSA (0.1 g) was stirred at room temperature in solvent-free condition.e progress of the reaction was monitored by TLC or GC.Aer completion of the reaction, CH 2 Cl 2 was added, the mixture was �ltered, and water (10 mL) was added.e mixture was extracted with CH 2 Cl 2 (2 × 12 mL), and the organic layers were separated, washed with saturated NaHCO 3 (2 × 15 mL) and water (10 mL), and dried over anhydrous MgSO 4 .Evaporation of the solvent followed by column chromatography on silica gel afforded the pure product.

Results and Discussion
Several experiments were carried out to optimize the amount of SSA and found that 0.1 g is the best condition.Reactions do not take place with less than 0.1 g, and with more SSA, rates will remain steady.
e reaction condition was standardized aer conducting the acetylation of 4-chloroaniline (1.0 mM) with Ac 2 O (2.0 mM) in the presence of SSA (0.1 g) using various solvents at room temperature (Table 1).Since the 98% yield of 4chloroacetanilide was obtained under neat conditions, the reactions continued under solvent-free condition.
To �nd out the efficiency of acylating agents, 4chloroaniline was chosen as a representative electron-de�cient aniline and treated with various acylating agents such as ethyl acetate, acetic acid, vinyl acetate, acetyl chloride, and Ac 2 O in the presence of SSA (0.1 g) at room temperature under solvent-free conditions ( en, the acylation of different types of phenols, amines, and sulfur-containing compounds was carried out with Ac 2 O (1 : 2, the mole ratio of substrate to Ac 2 O) in the presence of SSA (0.1 g) at room temperature in solvent-free condition (Table 4).All the products e present procedure is chemoselective for the acetylation of bifunctional are known and were characterized by spectroscopic methods.compounds containing -NH 2 and -OH groups.So, the selective acetylation of -NH 2 group of ortho-or para-aminophenol was observed even with two equivalents of Ac 2 O to give the corresponding o-or p-hydroxyacetanilide. is might be due to the more nucleophilicity of -NH 2 group rather than -OH group.
Deactivated substrates could also be acetylated rapidly.For example, strongly deactivated 2-nitroaniline and 3nitroaniline (Table 4, entries 13 and 14) quantitatively afforded the corresponding acetates within 5-10 min.Again, we observed that 4-nitrophenol (Table 4, entry 9) was converted to the acetate derivatives much faster compared to the earlier reported procedure [5].
e exclusive formation of acylated products in quantitative yields is a signi�cant achievement indicating the capability of the applied procedure.
Table 5 shows the efficiency of SSA compared with those catalysts which were used before.Most of the other catalysts either had lesser yields or needed longer reaction time for completion.
Journal of Chemistry 3 T 4: Acylation of phenols, amines, and thiols using Ac2O in the presence of SSA under solvent-free conditions at room temperature.

Conclusions
We used SSA as an active and capable heterogeneous catalyst for the acylation of phenols, amines, and thiols.Moreover, this catalyst offers a mild reaction condition with short reaction times under the neat condition.Also, the present procedure is chemoselective for the N-acetylation of bifunctional compounds containing -NH 2 and -OH groups.In addition, deactivated substrates could also be acetylated rapidly (Table 3, entries 13 and 14).

Table 2 )
. e best result was obtained in 98% yield with Ac 2 O, so the acetylation continued with Ac 2 O as a best acylating agent.ereaction of 2-naphthol, 4-chloroaniline, and 4bromobenzenethiol (1.0 mM) with different mole ratios of Ac 2 O (1.0, 1.2, 1.5, 1.7, and 2.0) was carried out in the T 2: Acylation of 4-chloroaniline (A) by different acylating reagents (B) with SSA under solvent-free conditions at room temperature.
Reusability of the Catalyst.We also investigated the reusability of the catalyst.For this purpose aer completion of the reaction (4-chloroaniline + ethyl acetate + SSA), CH 2 Cl 2 was added to the reaction mixture.e catalyst was separated by a simple �ltration, washed with CH 2 Cl 2 , and used for four successive reactions without signi�cant loss of activity.e results of the �rst experiment and subsequent reactions were almost consistent in the yields.