Rearrangement of 4-Amino-3-halo-pyridines by Nucleophilic Aromatic Substitution

Abstract

The reaction of 3-halo-4-aminopyridines with acyl chlorides and triethylamine is described. The pyridin-4-yl α-substituted acetamide products were obtained in moderate to high yields. The presented rearrangement reaction, in which the presumed N-acylated intermediate reacts intramolecularly via nucleophilic aromatic substitution, results in a formal two-carbon insertion.

The Truce–Smiles rearrangement and related reactions: a review

“…Researchers have typically chosen to prepare an aryl ether substrate by Williamson ether synthesis 30,31,[44][45][46] or an aniline substrate, 47,48 with judicious choice of a base that can subsequently form the carbanion intermediate to instigate the TruceSmiles rearrangement. In one unusual example 43 (Scheme 7), a benzyne intermediate is used to form the sulfonamide bond linking the nucleophilic and electrophilic portions of the substrate 14 with concurrent production of the carbanion nucleophile.…”

“…21 Similarly, there are numerous examples of successful rearrangements of 4-substituted pyridine substrates in the literature. 23,46,48,52,95 In keeping with theory, examples of the successful rearrangement of 3-substituted pyridine substrates 22,52 are the rarest for For the substrates studied by Kündig's research group, the 4-substituted pyridine substrate, 74, appears to be the superior rearrangement substrate as evidenced by a high yield of product and a brief reaction time, followed by 2-substituted pyridine substrate, 70, with the 3-substituted pyridine, 72, as the poorest substrate (Scheme 25). The comparison of these three analogous substrates is complicated by the tandem nature of the reaction, with the activating effects of the second nucleophilic aromatic substitution reaction predicted to be the opposite of the first substitution (Truce-Smiles rearrangement) in the sequence.…”

“…Substrates featuring X = N may be anilides, 48,100 isolated as the less substituted amide or trapped by an electrophile, 52 or alternatively anilines, 47 isolated as the amine. One unusual example 101 of a substrate was a N-arylated pyrrole, 105, that yielded the N-unsubstituted pyrrole, 107, on rearrangement (Scheme 33).…”

“…58,61 Examples of Truce-Smiles rearrangements occurring through the formation of 4-membered ring spirocyclic Meisenheimer adducts are also relatively uncommon. 36,39,48,52,95 Each of the examples shown in Fig. 7 arise from isolated, seemingly adventitious, observations from a variety of research groups, making it difficult to draw conclusions from these non-systematic, inconsistent examples.…”

“…However, in at least one of these examples, increased substitution at the nucleophilic carbon position was observed to decrease reactivity. 48 In the absence of evidence of the existence of these putative intermediate structures, it remains difficult to draw clear conclusions.…”