Synthesis of Substituted t-Butyl 3-Alkyloxindole-3-carboxylates from Di-t-butyl (2-Nitrophenyl)malonates

Sumiyoshi, Takaaki; Yamai, Yu‐suke; Tanaka, Akio; Yajima, Tatsuo; Ishida, Kyoji; Natsutani, Itaru; Uesato, Shinichi; Nagaoka, Yasuo

doi:10.3987/com-17-s(t)2

HETEROCYCLES

2018

DOI: 10.3987/com-17-s(t)2

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Synthesis of Substituted t-Butyl 3-Alkyloxindole-3-carboxylates from Di-t-butyl (2-Nitrophenyl)malonates

Takaaki Sumiyoshi¹,

Yu‐suke Yamai²,

Akio Tanaka³

et al.

Abstract: -Using a novel tandem reduction-cyclization, we synthesized t-butyl 3-alkyloxindole-3-carboxylates from the di-t-butyl 2-alkyl-2-(2-nitrophenyl)-malonate. Introduction of an α-substituent to the di-t-butyl 2-(2-nitrophenyl)-malonates and addition of acid promoted reactivity.This methodology was successfully applied to gram-scale-synthesis of the t-butyl 3-methyloxindole-3-carboxylate 1 and 3-hydroxymethyl-3-methyloxindole 2 without silica gel column chromatography.

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Cited by 3 publications

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Synthesis of Lactams via a Chiral Phosphoric Acid-Catalyzed Aniline Cyclization

Horchar,

Dean,

Lake

et al. 2024

J. Org. Chem.

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The enantioenriched lactams disclosed in this work are synthesized concisely in four steps. In the penultimate reaction, a benzylamine species complexes with a chiral phosphoric acid to produce benzo-fused δ-lactams equipped with an all-carbon quaternary stereocenter. Partial and full reductions were carried out on the ester and amide moieties, and a Suzuki–Miyaura cross-coupling expanded the molecule from the aromatic ring. Finally, our method was successful at a >1 g scale, indicating that the method has important practical use.

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Synthesis of Lactams via a Chiral Phosphoric Acid-Catalyzed Aniline Cyclization

Horchar,

Dean,

Lake

et al. 2024

J. Org. Chem.

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show abstract

Design, synthesis and evaluations of spiro‐fused benzoxaborin derivatives as novel boron‐containing compounds

et al. 2019

Self Cite

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Drug design using boron‐containing heterocycles has attracted a great deal of attention because these compounds are believed to possess high biological activity. However, information on the synthetic methodology and pharmacokinetic profiling of boron‐containing compounds is limited. In this study, we provide a new synthetic route for preparation of spiro‐fused benzoxaborin derivatives and investigate their in vitro pharmacokinetic properties. Our efforts led to the successful construction of a chemical library of spiro‐fused benzoxaborin derivatives with appropriate physicochemical and in vitro pharmacokinetic properties for oral drugs. These results indicate that the synthesized boron‐containing compounds are therefore eligible for classification in a novel chemical library.

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Asymmetric Synthesis of t-Butyl 3-Alkyl-oxindole-3-carboxylates via Chiral Phosphoric Acid Catalyzed Desymmetrization of Di-t-butyl 2-Alkyl-2-(2-aminophenyl)malonates

Sumiyoshi¹,

Ishida²,

Shimizu³

et al. 2019

HETEROCYCLES

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We describe the asymmetric desymmetrization of di-t-butyl 2-alkyl-2-(2-aminophenyl)malonates to prepare enantioenriched t-butyl 3-alkyl-oxindole-3-carboxylates using (S)-TRIP, a chiral phosphoric acid.Optimization study increased the enantioselectivity up to 66% ee. Chiral 3,3-disubstituted oxindoles are often used for synthesis of natural products or bioactive compounds. 1 In particular, asymmetric synthesis of alkyl 3-alkyl-oxindole-3-carboxylates has attracted a great deal of attention due to chirality of these compounds, which often influences biological activity. 2 For example, Kozlowski and co-workers reported asymmetric synthesis of oxindoles using Claisen rearrengement. 3 Park and co-workers, on the other hand, reported the use of enantioselective alkylation at the -position of malonates followed by lactamization. 4 Although cyclization reaction of dialkyl 2-alkyl-2-(2-aminophenyl)malonates is one of the most frequently used methodologies for the synthesis of alkyl 3-alkyl-oxindole-3-carboxylates, 5 there is no enantioselective synthesis of alkyl 3-alkyl-oxindole-3-carboxylates using asymmetric desymmetrization of dialkyl 2-alkyl-2-(2-aminophenyl)malonates. Therefore, it is important to develop a novel effective methodology toward the synthesis of the desired oxindoles via asymmetric desymmetrization of dialkyl 2-alkyl-2-(2-aminophenyl)malonates, which can concisely be synthesized from the cost-effective dialkyl malonates. Here, we describe the asymmetric synthesis of oxindole 1 using chiral phosphoric acid catalyzed asymmetric desymmetrization of the symmetric di-t-butyl malonate 2 (Figure 1). To the best of

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Synthesis of Substituted t-Butyl 3-Alkyloxindole-3-carboxylates from Di-t-butyl (2-Nitrophenyl)malonates

Cited by 3 publications

References 50 publications

Synthesis of Lactams via a Chiral Phosphoric Acid-Catalyzed Aniline Cyclization

Synthesis of Lactams via a Chiral Phosphoric Acid-Catalyzed Aniline Cyclization

Design, synthesis and evaluations of spiro‐fused benzoxaborin derivatives as novel boron‐containing compounds

Asymmetric Synthesis of t-Butyl 3-Alkyl-oxindole-3-carboxylates via Chiral Phosphoric Acid Catalyzed Desymmetrization of Di-t-butyl 2-Alkyl-2-(2-aminophenyl)malonates

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