During the multistep synthesis of natural products, the efficiency of the synthetic protocol employed often depends largely on protection and deprotection of the functional groups. To this end, protecting groups have played a crucial role in the synthesis of complex natural products ^[1]. Acetylation and formylation of hydroxy groups are the most widely used transformations in organic synthesis ^{[2, 3, 4]}.

Amongst protecting groups for alcohols, esters are the most important with acetate being the simplest and easiest to use. Acetylation is usually performed with reagents such as acetic anhydride or acetyl chloride in the presence of variety of acidic or basic catalysts ^[5].

Formylation is also a very important process in organic chemistry. O-Formylation is the method of choice for protecting an alcoholic group in a complex synthetic sequence because deformylation can be affected selectively in the presence of acetate or other ester protecting groups ^{[6, 7, 8]}.

Several acetylation and formylation procedures for alcohols have been reported over the years ^{[9, 10, 11, 12, 13, 14]}, but these methods suffer from some disadvantages, such as heavy metal contamination, high temperature, formation of undesirable or toxic byproducts, expensive reagents, or long reaction times ^{[15, 16, 17, 18]}. These issues stimulated us to research a simple, efficient, and safe catalyst for the acetylation and formylation of alcohols. In this regard, a group of compounds entitled N-halo reagents is widely used in fine organic synthesis ^[19].

Chemicals were purchased from Fluka, Merck, and Aldrich. The formylated and acetylated products were characterized by comparison of their spectral (IR, ¹H NMR, and ¹³C NMR) and physical data with those of authentic samples.

To the stirred mixture of 4-tert-butyl benzyl alcohol (1 mmol, 0.164 g) and ethyl formate (2 mL), tribromo melamine (0.1 mmol) was added without additional solvents. The resulting mixture was stirred at room temperature for 30 min. The reaction was monitored by TLC. On completion of reaction, the product was extracted with CH₂Cl₂ (5 mL × 4). The organic layer was separated, dried over anhydrous Na₂SO₄ (1.5 g), and concentrated under reduced pressure. Finally, the organic solvents were evaporated, and 4-tert-butylbenzyl formate was obtained in 92% yield. The identity of the product was confirmed by comparing the physical and spectral data with those of the known compound.

Tribromo melamine (0.1 mmol) was added to a solution of 3-fluorobenzyl alcohol (0.126 g, 1 mmol) and acetic anhydride (0.204 g, 2 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 1 h (the progress of the reaction was monitored by TLC). On completion of the reaction, water (5 mL) and then 5% NaHCO₃ (5 mL) was added to the mixture with stirring, and the product was extracted with CH₂Cl₂ (5 mL × 4). The organic layer was dried over anhydrous Na₂SO₄ (1.5 g). Finally, the organic solvents were evaporated, and 3-fluorobenzyl acetate was obtained in 86% yield.

Following our previous work in developing new methods for the protection of the hydroxy group ^{[20, 21, 22, 23]}, an effective procedure for the acetylation and formylation of alcohols with acetic anhydride and ethyl formate in the presence of catalytic amounts of tribromo melamine at room temperature (Scheme 1) has been developed.

Scheme 1. Formylation and acetylation of alcohols.

To find the optimal conditions for the formylation of alcohols by this method, we selected 4-bromobenzyl alcohol as a model substrate and treated it with ethyl formate in the presence of different amounts of tribromo melamine at room temperature. We found that 0.05 equivalents of tribromo melamine gave the highest yield of the respective alkyl formate after 60 min at room temperature (Table 1, entry 5). The results clearly show that the tribromo melamine is effective for this transformation, whereas, in its absence, the reaction fails to initiate even after 24 h (Table 1, entry 6). Additionally, 4-bromobenzyl alcohol was used as a model substrate for acetylation (Table 1, entries 7-12). The reaction was monitored with different amounts of catalyst. Increasing the loading of tribromo melamine from 0.01 mmol to 0.05 mmol resulted in a considerable improvement of the yield from 22% to 95% (Table 1, entries 7 and 11). The acetylation reaction was also carried out in the absence of catalyst. Again, the reaction had not initiated after 24 h (Table 1, entry 12).

Table 1 Optimization of the amount of tribromo melamine in the reaction of 4-bromobenzyl alcohol with ethyl formate or acetic anhydride. Entry Catalyst amount (mmol) Yield a (%) 1 0.01 13 2 0.02 40 3 0.03 41 4 0.04 56 5 0.05 99 6 No catalyst Trace 7 0.01 22 8 0.02 28 9 0.03 30 10 0.04 57 11 0.05 95 12 No catalyst Trace Reaction conditions: 4-bromobenzyl alcohol 1 mmol, ethyl formate 2 mL or acetic anhydride 2 mmol, room temperature. a Yields refer to isolated pure products.

Table 1 Optimization of the amount of tribromo melamine in the reaction of 4-bromobenzyl alcohol with ethyl formate or acetic anhydride.

To find the best solvent for the formylation, the model reaction was performed in a number of solvents, and moderate to poor yields of the corresponding alkyl formates were obtained (Table 2, entry 2-6). A far higher yield was obtained under solvent-free conditions (Table 2, entry 1).

Table 2 Effect of solvent on the conversion of 4-bromobenzyl alcohol to the corresponding formate or acetate. Entry Solvent Time (min) Yield a (%) 1 Solvent-free 1 h 99 2 Acetone 24 h 40 3 Dichloromethane 24 h 54 4 Acetonitrile 24 h 9 5 Ethyl acetate 24 h 58 6 Chloroform 24 h 23 7 Solvent-free 240 96 8 Acetone 180 95 9 Dichloromethane 20 95 10 Acetonitrile 165 83 11 Ethyl acetate 202 99 12 Chloroform 106 97 Reaction conditions: substrate:ethyl formate/acetic anhydride = 1 mmol/2 mmol, catalyst 0.05 mmol, solvent 5 mL. a Yields refer to isolated pure products.

Table 2 Effect of solvent on the conversion of 4-bromobenzyl alcohol to the corresponding formate or acetate.

The acetylation reaction was also investigated in various solvents; the model reaction consisted of 1 mmol of 4-bromobenzyl alcohol with acetic anhydride (2 mmol) using 0.05 mmol of tribromo melamine as the catalyst (Table 2, entry 7-12). Dichloromethane was found to be most effective solvent giving high yield with comparatively low reaction time (Table 2, entry 9).

Therefore, we employed these optimized conditions for the formylation (0.05 mmol tribromo melamine, solvent-free) and acetylation (0.05 mmol tribromo melamine in dichloromethane as the solvent) of various alcohols into the corresponding formates (Table 3) and acetates (Table 4), respectively.

Table 3 Formylation of alcohols. Entry Substrate Catalyst amount (mmol) Time (min) Yield a (%) 1 4-Chlorobenzyl alcohol 0.05 80 97 2 Benzyl alcohol 0.05 30 99 3 4-Fluorobenzyl alcohol 0.20 44 98 4 3-Fluorobenzyl alcohol 0.20 48 96 5 2,4-Dichlorobenzyl alcohol 0.15 70 99 6 4-Nitrobenzyl alcohol 0.20 120 50 7 Benzhydrol 0.15 55 93 8 4-t-Butylbenzyl alcohol 0.10 30 92 9 4-Bromobenzyl alcohol 0.05 60 99 10 3-Pyridinmethanol 0.05 180 23 Reaction conditions: alcohol 1 mmol, ethyl formate 2 mmol. a Yields refer to isolated pure products.

Table 3 Formylation of alcohols.

Table 4 Acetylation of alcohols. Entry Substrate Catalyst amount (mmol) Time (min) Yield a (%) 1 2-Chlorobenzyl alcohol 0.05 45 99 2 Benzyl alcohol 0.05 15 99 3 4-Fluorobenzyl alcohol 0.10 50 99 4 3-Fluorobenzyl alcohol 0.10 60 86 5 2,4-Dichlorobenzyl alcohol 0.15 12 84 6 4-Nitrobenzyl alcohol 0.20 95 97 7 Benzhydrol 0.10 60 93 8 4-tert-Butylbenzyl alcohol 0.10 40 98 9 4-Bromobenzyl alcohol 0.05 20 95 10 3-Pyridinmethanol 0.10 80 86 Reaction conditions: alcohol 1 mmol, acetic anhydride 2 mmol. a Yields refer to isolated pure products.

Table 4 Acetylation of alcohols.

Different types of alcohols, having both electron withdrawing and donating groups, were formylated with ethyl formate in the presence of a catalytic amount of tribromo melamine under solvent-free conditions in good to high yields (Table 3, entries 1-9).

Benzyl alcohols, phenols, and non-benzyl alcohols groups were subjected to the formylation reaction to investigate the chemoselectivity of the proposed system. The formylation of phenols and non-benzyl alcohols did not occur under our conditions, and phenols or non-benzyl hydroxyl groups remained unaffected during the reaction (Scheme 2).

Scheme 2. Chemoselectivity of formylation.

As can be seen in Table 4, both electron-withdrawing and electron-donating substituents on the alcohols could be employed in the synthesis of acetates.

Our experiments also indicated that non-benzyl alcohols were not acetylated under these conditions. This catalytic acetylating system is also chemoselective so that the acetylation of benzyl alcohols was selective in the presence of phenols (Scheme 3). A possible mechanism of these reaction systems is shown in Scheme 4.

We have developed a new strategy for the acetylation and formylation of alcohols with acetic anhydride and ethyl formate in the presence of catalytic amounts of tribromo melamine at room temperature. Our method involves mild reaction conditions, using very simple and accessible starting materials and solvents, as well as an inexpensive and non-toxic catalyst.

Acknowledgements

Financial support from the Ilam University, Ilam, Iran is gratefully acknowledged.