Lithiation–Electrophilic Substitution of <i>N</i>‐Thiopivaloylazetidine

Hodgson, David M.; Kloesges, Johannes

doi:10.1002/anie.201000058

Cited by 61 publications

(24 citation statements)

References 26 publications

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“…Arylation of the seven-membered ring (azepane) gave arylated product 2c in 54% yield and 98.5:1.5 er. Lithiation of azetidine and subsequent trapping with various electrophiles has been reported earlier with good enantioselectivity for methylation (91:9 er) 30,31 . However, C–H arylation of azetidine has not been demonstrated with either α -lithiation or our previous C–H activation protocol 10 .…”

supporting

confidence: 53%

Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

et al. 2016

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Saturated aza-heterocycles are highly privileged building blocks that are commonly encountered in bioactive compounds and approved therapeutic agents. These N-heterocycles are also incorporated as chiral auxiliaries and ligands in asymmetric synthesis. As such, development of methods to functionalize the α-methylene C–H bonds of these systems enantioselectively is of great importance, especially in drug discovery. Currently, enantioselective lithiation with (–)-sparteine followed by Pd(0) catalyzed cross coupling to prepare α-arylated amines is largely limited to pyrrolidines. Here we report a Pd(II)-catalyzed enantioselective α-C–H coupling of a wide range of amines, including ethyl amines, azetidines, pyrrolidines, piperidines, azepanes, indolines, and tetrahydroisoquinolines. Chiral phosphoric acids are demonstrated as effective anionic ligands for the enantioselective coupling of methylene C–H bonds with aryl boronic acids. This catalytic reaction not only affords high enantioselectivities, but also provides exclusive regioselectivity in the presence of two methylene groups in different steric environments.

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confidence: 53%

Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

et al. 2016

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“…19 Alternatively, the thioamide 1 can be converted to amide 17 by oxidation with silver(II)-salts in nearly quantitative yield.…”

mentioning

confidence: 99%

α-Arylation of Saturated Azacycles and N-Methylamines via Palladium(II)-Catalyzed C(sp³)–H Coupling

et al. 2015

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“…The rarely studied N-thiopivaloyl group plays a crucial role in mediating efficient α-lithiation (Scheme 7.14). By using a chiral ligand, such as (−)-sparteine, modest level of enantioselectivity has been observed for the lithiation/trapping sequence (er 80/20, E = Me) [20]. α-Lithiation of Nthiopivaloylazetidin-3-ol and subsequent electrophile trapping leads to 2-substituted 3-hydroxyazetidine derivatives with generally good trans-diastereoselectivity, with the exception of deuteration, which furnishes the cis-diastereomer [21].…”

Section: Four-membered Rings: Lithiated Azetidinesmentioning

confidence: 99%

Nitrogen‐Bearing Lithium Compounds in Modern Synthesis

Degennaro¹,

Musio²,

Luisi³

2014

Lithium Compounds in Organic Synthesis

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IntroductionNitrogen-containing compounds are ubiquitous and are extremely important in synthesis. This chapter reports some general aspects of the generation, structure, and reactivity of nitrogen-bearing organolithiums showing the progress made over the last decade. The chapter does not cover comprehensively the field but the aim is to provide the reader with useful information on the generation, reactivity, and potential in synthesis of this kind of lithiated intermediates.Throughout the chapter, the name amino-organolithiums is used to describe reactive intermediates lithiated at sp 3 -hybridized carbon atoms adjacent (α) to a nitrogen atom that could be included also in a ring. Amino-organolithiums can be generated mainly in three different ways: (i) deprotonation of a parent amine or its derivative; (ii) transmetallation by using an alkyllithium; and (iii) reductive cleavage of C-heteroatom bond (e.g., C-S). Each way has advantages and disadvantages and in some cases they complement each other (Scheme 7.1).Direct deprotonation is a widely used strategy to generate amino-organolithiums even in chiral form, while tin-lithium exchange reactions are preferred when direct deprotonations are difficult (high kinetic barrier) or regiochemical issues apply. Concerning the direct deprotonation of amines, this is not a simple task because the corresponding lithiated intermediates suffer from destabilizing interactions that make this reaction very difficult unless a ''stabilizing group'' (SG) is introduced either on the nitrogen atom or on the lithium-bearing carbon (Scheme 7.2).The SG (Scheme 7.2) has a pivotal role, either reducing the kinetic barrier in the hydrogen/lithium permutation or stabilizing the organolithium mesomerically or by coordination. For these reasons, often, amino-organolithiums are classified as stabilized or unstabilized. The chemistry of unstabilized amino-organolithiums has been so far less developed however, lithiation of simple tertiary amines could be accomplished by two main strategies: (i) by tin/lithium exchange reaction and (ii) by deprotonation of quaternary ammonium complexes (Scheme 7.3).

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Lithiation–Electrophilic Substitution of N‐Thiopivaloylazetidine

Cited by 61 publications

References 26 publications

Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

α-Arylation of Saturated Azacycles and N-Methylamines via Palladium(II)-Catalyzed C(sp³)–H Coupling

Nitrogen‐Bearing Lithium Compounds in Modern Synthesis

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Lithiation–Electrophilic Substitution of N‐Thiopivaloylazetidine

Cited by 61 publications

References 26 publications

Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

α-Arylation of Saturated Azacycles and N-Methylamines via Palladium(II)-Catalyzed C(sp3)–H Coupling

Nitrogen‐Bearing Lithium Compounds in Modern Synthesis

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α-Arylation of Saturated Azacycles and N-Methylamines via Palladium(II)-Catalyzed C(sp³)–H Coupling