Kinetic resolution of alkyne-substituted quaternary oxindoles via copper catalysed azide–alkyne cycloadditions

Brittain, William D. G.; Buckley, Benjamin R.; Fossey, John S.

doi:10.1039/c5cc04886a

Cited by 46 publications

(32 citation statements)

References 64 publications

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“…Since the first step is the formation of a N,C-dianion, attempts for the selective 3-alkylation of 3-monosubstituted oxindoles 8 with less than 2.0 eq BuLi are always low-yielding. Accordingly, 3-ethylation of 3-methyloxindole (1.0 eq BuLi, 3 eq LiCl, 5.0 eq EtI, THF) [26] or 3-propargylation of 3-ethyloxindole (1.2 eq BuLi, 1.0 eq propargyl bromide, THF) [27] gave, after chromatographic purification, 25% and 55% yields, respectively. Use of 2.0 eq BuLi led to better results: 3-methyloxindole was 3-methylated (2.0 eq BuLi, 9.4 eq MeI) in 75% yield after chromatographic purification [28].…”

Section: Introductionmentioning

confidence: 99%

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

2016

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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.

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Section: Introductionmentioning

confidence: 99%

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

2016

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“…Since simple alkyl amine derivatives of 1 (positions R 3 and R 4 , Fig. 1) were chronologically first available to this project as single enantiomers, azetidine 1a was selected for initial investigation (Table 1, entry 1).…”

Section: Resultsmentioning

confidence: 99%

Rigid and concave, 2,4-cis-substituted azetidine derivatives: A platform for asymmetric catalysis

Yoshizawa¹,

Feula²,

Male³

et al. 2018

Preprint

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A series of single enantiomer, 2,4-cis-disubstituted amino azetidines were synthesised and used as ligands for copper-catalysed Henry reactions of aldehydes with nitromethane. Optimisation of ligand substituents and the reaction conditions was conducted. The enantiomeric excess of the formed products was highest when alkyl aldehydes were employed in the reaction (>99% e.e.). The absolute stereochemistry of one representative azetidine derivative salt was determined by analysis of the Flack parameter of an XRD single crystal structure. The origin of selectivity in catalysis was investigated computationally, revealing the importance of the amino-substituent in determining the stereochemical outcome. A racemic platinum complex of a cis-disubstituted azetidine is examined by XRD single crystal structure analysis with reference to its steric parameters, and analogies to the computationally determined copper complex catalyst are drawn.

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“…A complicating factor in the synthesis of hierarchically structured polymers is that techniques for quantitative analysis of the efficiency of polymer coupling reactions are generally lacking. While techniques, such as Nuclear Magnetic Resonance (NMR) and gas chromatography (GC), are often employed to characterize the CuAAC reactions of low‐molecular weight molecules, these techniques are generally unsuitable for studying the efficiency of polymer coupling since their sensitivities diminish for macromolecules of high‐molecular weight. Size exclusion chromatography (SEC) has been widely employed to monitor the CuAAC reactions of macromolecules, however, these analyses often do not take into account the functionality of the building blocks and are usually based on a polystyrene standard without application of universal calibration.…”

Section: Introductionmentioning

confidence: 99%

How good is CuAAC “click” chemistry for polymer coupling reactions?

Leophairatana

Silva

Koberstein

2017

J. Polym. Sci. Part A: Polym. Chem.

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ABSTRACT:1 H NMR and SEC analyses are used to investigate the overall efficiency of Copper Catalyzed Azide Alkyne Cycloaddition (CuAAC) "click" coupling reactions between alkyneand azide-terminated polymers using polystyrene as a model. Quantitative convolution modeling of the entire molecular weight distribution is applied to characterize the outcomes of the functional polymer synthesis reactions (i.e., by atom transfer radical polymerization), as well as the CuAAC coupling reaction. Incomplete functionality of the azide-terminated polystyrene ($92%) proves to be the largest factor compromising the efficacy of the CuAAC coupling reaction and is attributed primarily to the loss of terminal bromide functionality during its synthesis. The efficiency of the S N 2 reaction converting bromide to azide was found to be about 99%. After taking into account the influence of non-functional polymer, we find that, under the reaction conditions used, the efficiency of the CuAAC coupling reaction determined from both techniques is about 94%. These inefficiencies compromise the fidelity and potential utility of CuAAC coupling reactions for the synthesis of hierarchically structured polymers. While CuAAC efficiency is expected to depend on the specific reaction conditions used, the framework described for determining reaction efficiency does provide a means for ultimately optimizing the reaction conditions for CuAAC coupling reactions.

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Kinetic resolution of alkyne-substituted quaternary oxindoles via copper catalysed azide–alkyne cycloadditions

Abstract: The synthesis and kinetic resolution of quaternary oxindoles through copper catalysed azide-alkyne cycloadditions is presented. Selectivity factors (s) up to 22.1 ± 0.5 are reported. Enantioenriched alkynes and triazoles were obtained in ≥80% enantiomeric excess (e.e.).

Cited by 46 publications

References 64 publications

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

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

Rigid and concave, 2,4-cis-substituted azetidine derivatives: A platform for asymmetric catalysis

How good is CuAAC “click” chemistry for polymer coupling reactions?

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