(Benzoylamino)methyl 4-[(Benzoylamino)methoxy]benzoate

Abstract: In this note, two procedures for the synthesis of (benzoylamino)methyl 4-[(benzoylamino)methoxy]benzoate ( 3 ) are presented. The first procedure is carried out in dioxane/water using benzoylaminomethyl-4-hydroxybenzoate, while the second one employs a suspension of 4-hydroxybenzoic acid in dioxane. In both procedures, benzamidomethyl triethylammonium chloride is used for the benzamidomethylation reaction. Keywords: benzamidomethyl ester; synthesis Methyl 4-methoxybenzoate (also known as methyl anisate) is a white crystalline powder, soluble in alcohol and ether, but insoluble in water. In the nature, it occurs as a volatile compound in mushroom species and plants [1–5]. These types of esters are used as pharmaceutical intermediates and take part in many organic syntheses [6,7]. For example, a new imaging compound, [(125)I]iodoDPA-713, was synthesized in several steps from methyl 4-methoxybenzoate as a tool for quantification of inflammation in preclinical models [6]. Nowadays, methyl 4-methoxybenzoate has application in the flavor and perfume industry as synthetic flavoring substance due to its sweet herbal anis aroma, impressing lilac or magnolia [8,9]. In this note, the synthesis of a new compound, (benzoylamino)methyl 4-[(benzoylamino)methoxy]-benzoate (

Methyl 4-methoxybenzoate (also known as methyl anisate) is a white crystalline powder, soluble in alcohol and ether, but insoluble in water.In the nature, it occurs as a volatile compound in mushroom species and plants [1][2][3][4][5].These types of esters are used as pharmaceutical intermediates and take part in many organic syntheses [6,7].For example, a new imaging compound, [(125)I]iodoDPA-713, was synthesized in several steps from methyl 4-methoxybenzoate as a tool for quantification of inflammation in preclinical models [6].Nowadays, methyl 4-methoxybenzoate has application in the flavor and perfume industry as synthetic flavoring substance due to its sweet herbal anis aroma, impressing lilac or magnolia [8,9].
In this note, the synthesis of a new compound, (benzoylamino)methyl 4-[(benzoylamino)methoxy]benzoate (3), similar to methyl anisate, is reported.The synthesis of 3 was carried out by using (benzamidomethyl)triethylammonium chloride (2) as a reagent for benzamidomethylation.Although 2 is an excellent reagent for benzamidomethylation of phenols [10], in our previous work [11] we demonstrated that the phenol group at 4-hydroxybenzoic acid (4) cannot be benzamidomethylated with OPEN ACCESS 2 in aqueous media.The carboxylic group as a weak nucleophile in aqueous media does not react [12], but it deactivates the phenol group in the molecule of 4-hydroxybenzoic acid.However, once the carboxylic group is protected as in (benzoylamino)methyl 4-hydroxybenzoate (1), the hydroxyl group can be easily benzamidomethylated with 2 in aqueous media to obtain 3 (Scheme 1).
As presented in Scheme 1, the title compound can also be obtained directly from 4 in dioxane suspension of 2 at 50 °C.

Experimental
Compound 2 is not commercially available and it was synthesized as described previously [10].

(Benzoylamino)methyl 4-[(benzoylamino)methoxy]benzoate (3)
Procedure A To a mixture of 1 (0.310 g, 1.14 mmol), well powdered 2 (0.334 g, 1.23 mmol), dioxane (25 mL) and triethylamine (0.1 mL) was added water drop by drop, until a clear solution was obtained.The mixture was stirred for 10 h at room temperature and subsequently water was added until occurrence of a precipitate.The maximal yield of crude colorless crystals was 70%.The purification was performed firstly by dissolving the product in dioxane and by precipitation with water and then by recrystallization from ethyl acetate.

Procedure B
To a suspension of 2 (0.529 g, 1.95 mmol) in dioxane (10 mL) were added 4 (0.108 g, 0.78 mmol) and TEA (0.1 mL).The mixture was stirred and heated at 50 °C for 24 h.After cooling, water was Molbank 2011 M711 (Page 3) added until a white precipitate occurred.The colorless crystals were filtered off and purified as described in Procedure A. Maximum yield was 56%.

Scheme 1 .
Scheme 1. Synthetic routes to the title compound 3.