Literature Survey and Further Studies on the 3-Alkylation of N-Unprotected 3-Monosubstituted Oxindoles. Practical Synthesis of N-Unprotected 3,3-Disubstituted Oxindoles and Subsequent Transformations on the Aromatic Ring

Abstract

The paper provides a comprehensive review of the base-catalysed C3-alkylation of N-unprotected-3-monosubstituted oxindoles. Based on a few, non-systematic studies described in the literature using butyllithium as the deprotonating agent, an optimized method has now been elaborated, via the corresponding lithium salt, for the selective C3-alkylation of this family of compounds. The optimal excess of butyllithium and alkylating agent, and the role of the halogen atom in the latter (alkyl bromides vs. iodides) were also studied. The alkylation protocol has also been extended to some derivatives substituted at the aromatic ring. Finally, various substituents were introduced into the aromatic ring of the N-unprotected 3,3-dialkyloxindoles obtained by this optimized method.

Study on the Alkylation Reactions of N(7)-Unsubstituted 1,3-Diazaoxindoles

“…Deprotonation with BuLi leading to the formation of the corresponding dianions was performed at −78 °C in each case, although with different amounts of BuLi (2.4–3.0 eq.). Then, contrary to our earlier observations with 3-monoalkyloxindoles ( 9 ) where MeI was also added at −78 °C [ 17 ], for 1,3-diazaoxindoles 24a – c we found that addition of MeI had to be carried out at −20 °C so that starting materials 24a – c are fully consumed. Finally, the reaction mixture was allowed to warm to ambient temperature.…”

“…As demonstrated by the reactions carried out using NaOH at our laboratory and by the procedures described in the literature using sodium, potassium or cesium bases for the deprotonation of 1,3-diazaoxindoles, selective alkylation at the C (5) position could not be achieved. Therefore, we continued our efforts by applying BuLi as the base in the alkylation reactions, which proved to be the optimal base in the analogous regioselective C (3)-alkylation reactions of N -unprotected oxindoles, particularly for the introduction of a second substituent into the carbonyl-adjacent C (3) position of N -unprotected 3-monoalkyloxindoles 9 ( Scheme 2 ) [ 17 , 39 ].…”

“…The presence of the hydroxy moiety in products 29a – c renders further functionalizations possible thereby making these compounds valuable synthetic building blocks. An analogous oxidative side reaction via the corresponding hydroperoxide is also described in the oxindole family [ 42 ], and the corresponding 3-hydroxy derivatives in the oxindole series were also synthesised at our laboratory [ 17 ].…”

“…In continuation of our studies on the monoalkylation at the C (3) position of N -unprotected oxindole ( 1 ) [ 14 , 15 , 16 ] to give 3-alkyloxindoles 9 and on the selective introduction of the second alkyl group, without N -alkylation to afford N -unprotected 3,3-dialkyloxindoles 10 ( Scheme 2 ) [ 17 ], we now aimed to elaborate a method for the introduction of two different alkyl groups into the structurally related carbonyl-adjacent C (5) site of N -unprotected 1,3-diazaoxindoles 6 .…”

Practical, scalable, and transition metal-free visible light-induced heteroarylation route to substituted oxindoles

“…Existing synthetic methods mainly rely on the use of preexisting oxindole cores to form 3,3′-disubstituted oxindoles via a typical functionalization step. 11 In addition, cyclization reactions represent widely used strategies for the construction of oxindole motifs. However, these methods inherently require an ortho -functionalized aryl group and 2-substituted activated anilides ( Fig.…”