The Ullmann Coupling between 2-Chlorobenzoic Acids and Amino Acids; A Valuable Reaction for Preparing 2-Substituted 1-Acetyl-1H-indol-3-yl Acetates­

Abstract

Substituted 3-acetoxy-1-acetyl-1H-indoles were pre- pared by condensing 2-chlorobenzoic acids with amino acids under Ullmann conditions in good yields, and further cyclodecarboxyla- tion using the Rossing method in moderate to good yields. N,O-Diacetylindoxyls (1-acetyl-1H-indol-3-yl acetates, 3-acetoxy-1-acetyl-1H-indoles) are present as precursors of some aglicons in chromogenic compounds that are very useful in the identification of various microorganisms. 1-3 However, 2-substituted 3-acetoxy-1-acetyl-1H-indoles are rarely found in literature and there are no procedures available that describe the synthesis of these compounds from the corresponding unactivated amino acid and 2- chlorobenzoic acids by the Ullman procedure. Neverthe- less, 2-substituted 3-acetoxy-1-acetyl-1H-indoles have been used as the starting point for the preparation of 2- substituted 1-acetyl-1,2-dihydro-3H-indol-3-ones. 4 On the other hand, only one compound, 3-acetoxy-1- acetyl-2-methyl-1H-indole, has been prepared from the corresponding N-acetylated 2-((carboxymethyl)ami- no)benzoic acid, but it was not prepared using the Ullman conditions. 4 In previous work we reported a simple two-step procedure for the preparation of 3-acetoxy-1-acetyl-6-chloro-1H-in- dole from 2,4-dichlorobenzoic acid and an unactivated amino acid in good yield. 5 Encouraged by this result, we decided to carry out the preparation of other substituted 3- acetoxy-1-acetyl-1H-indoles starting from the corre- sponding 2-chlorobenzoic acids. 6 These papers made us think about the possibility of using the same procedure to prepare 2-substituted 3-acetoxy-1-acetyl-1H-indoles 6 from 2-chlorobenzoic acids 1 and 2-substituted amino acids 2 or 5-aminopentanoic acid (3). We started by using the same reaction conditions given in previous papers and using 2-chlorobenzoic acids 1a-d and amino acids 2a-c or 3 to give Ullman compounds, 2-((carboxymethyl)ami- no)benzoic acids 4a-g and 5a-c (Table 1) in very good yields. Subsequent Rossing cyclodecarboxylation of 4a-g allowed us to obtain 2-substituted 3-acetoxy-1-acetyl-1H- indoles 6a-g in moderate to good yields (Table 2).