Question

All academic manuscripts (journal articles, communications, etc.) have an introduction as a way to introduce the reader to the scientific problem that the paper addresses and describe the purpose of the experiment and also what has been done by others to give the reader some context. Write a 200-400 word introduction to nucleophilic acyl substitution reactions. You should find two recent (within the last three years) examples of nucleophilic acyl substitution reactions in journals and introduce those articles in your introduction.

Answer 1

Nucleophilic acyl substitution reaction (SNAc) is one type of substitution reaction (Scheme 1), where a nucleophile (e.g. an alcohol or amine) substitutes the leaving group of an acyl type derivative (e.g. an acid halide, anhydride, or ester).

Scheme 1. General scheme of SNAc reaction.

In 2019, Joshi and coworkers have shown the use of SNAc reaction for the synthesis of indole derivative which has important use in medicinal chemistry [Current Chemistry Letters, 2019, 8, 63]. Pyridine was used to facilitate nucleophilic acyl substitution reaction. Pyridine helps to trap the evolved HCl gas by forming pyridinium chloride salt. At the same time, it helps in the conversion of acid chloride derivative into more reactive species (pyridium adduct) which triggers nucleophilic acyl substitution reaction. With this approach, Joshi and coworkers obtained very good yield using a mild methodology (Scheme 2).

In another report of 2019, Tiwari and coworkers have shown the use of SNAc reaction to install benzotriazole leaving group for a practical synthesis of benzothiazoles which has an important role in medicinal chemistry [J. Heterocyclic Chem., 2019, 56, 275]. They showed a two-step synthetic procedure which consists SNAc reaction followed by benzotriazole ring cleavage under the free radical condition and subsequent cyclization via elimination of N2. In SNAc reaction, they used pyrrolidine as a nucleophile in the presence of triethylamine to substitute one of the easily removable benzotriazole moieties of bis(benzotriazolyl) methanethione.

Scheme 2. Recent examples of SNAc reactions.