Aza-oxindole synthesis via base promoted Truce–Smiles rearrangement

Abstract

A novel efficient NaOtBu-mediated protocol for the synthesis of 3,3-disubstituted aza-oxindoles proceeds via a Truce-Smiles rearrangement-cyclisation pathway.

The Truce–Smiles rearrangement and related reactions: a review

“…However, the intramolecular nature of the reaction might influence regioselectivity in the case of a benzyne mechanism leading it to appear regiospecific when it is instead just highly regioselective. In the study of a tandem Truce-Smiles rearrangement synthesis of aza-oxindoles, 52 Kündig and colleagues provided further evidence to discount the benzyne mechanism through the use of a pyridine substrate, 41, bearing deuterium substituents on the migrating aryl ring. As shown in Scheme 15, the experiment showed exclusive formation of the S N Ar product, 45, with no observation of any of the product 46 expected for the alternative benzyne mechanism.…”

“…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. 52 Reports of diazines as substrates of the Truce-Smiles rearrangement are rare, despite the theoretical prediction that they should provide excellent substrates. Scheme 26 shows an example of a successful rearrangement of a 2-pyrimidyl substrate, 76.…”

“…18,19,21,46,52,58,61,94 As an example of one of these substrates, Scheme 24 shows the successful rearrangement and tandem cyclization of a 2-substituted pyridine substrate, 67, that is also activated by the presence of a cyano substituent at an ortho-position relative to the leaving group. 21 Similarly, there are numerous examples of successful rearrangements of 4-substituted pyridine substrates in the literature.…”

“…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).…”