Asymmetric Deprotonation of <i>N</i>-Boc Piperidine: React IR Monitoring and Mechanistic Aspects

Stead, Darren; Carbone, Giorgio; O’Brien, Peter; Campos, Kevin R.; Coldham, Iain; Sanderson, Adam J.

doi:10.1021/ja102043e

Cited by 152 publications

(93 citation statements)

References 18 publications

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“…approximately at 1605 cm -1 , which we consider arises from the initial lithiated species 5aLi and 5cLi, or 12aLi and 12cLi. Recently reported in situ IR studies of the lithiation of a carbamate directly observed the "pre-lithiation complex" between the substrate and lithiating agent, [29] the existence of which had previously been deduced by kinetic studies on a related compound. [30] However, with ureas 5a and 5c we were unable to detect any transient intermediates between 5 and 5Li.…”

Section: In-situ Ir Spectroscopymentioning

confidence: 95%

The Mechanism of the Stereospecific Intramolecular Arylation of Lithiated Ureas: The Role of Li⁺ Probed by Electronic Structure Calculations, and by NMR and IR Spectroscopy

et al. 2011

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In situ NMR and IR spectroscopy studies were carried out on the rearrangement of lithiated N‐benzyl‐N′‐aryl ureas, which involves N‐to‐C aryl transfer with retention of configuration. The IR spectroscopy studies revealed that initial benzylic lithiation was followed by migration of the aryl ring to yield a lithiated urea product without a detectable dearomatised intermediate. Similar results were obtained by NMR spectroscopy, but when 1,3‐dimethyl‐3,4,5,6‐tetrahydro‐2(1H)‐pyrimidinone (DMPU) was added to the solvent mixture, a transient dearomatised intermediate was detectable during migration of a 1‐naphthyl ring. DFT calculations highlight the importance of coordinated lithium cations, and their migration from one site to another, in the rearrangement. Rearrangement is initiated by migration of a solvated lithium cation from the anionic centre of the starting organolithium to a site close the adjacent phenyl ring, allowing retentive attack of the anionic centre on the more remote ring with movement of the solvated lithium cation to the remote ring stabilising the developing negative charge. A short‐lived spirocyclic intermediate is predicted to undergo elimination by loss of the urea substituent, completing the migration. Coordination of the carbonyl group to a second solvated lithium cation appears to be essential for this step. Calculated shifts for this intermediate when a 1‐naphthyl ring is migrating are consistent with the transient signals observed by NMR spectroscopy. Alternative pathways involving (1) invertive migration and (2) attack on the urea C=O group were also calculated and were found to require significantly higher energy transition states.

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Section: In-situ Ir Spectroscopymentioning

confidence: 95%

The Mechanism of the Stereospecific Intramolecular Arylation of Lithiated Ureas: The Role of Li⁺ Probed by Electronic Structure Calculations, and by NMR and IR Spectroscopy

et al. 2011

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“…25 In situ IR spectroscopy was particularly useful here because it allowed the real-time monitoring of the reactions, providing instant feedback with regards to reaction progression, and was especially useful when reactions were conducted under air-and moisture-sensitive conditions. 26 It was, therefore, ideal for the investigation of the formal [4+2]-cycloaddition reaction as outlined in Eqn. 9, in order to gain mechanistic insight into this reaction.…”

Section: Proposed Mechanism For the Formal [4+2]-cycloadditionmentioning

confidence: 99%

Alternative tandem cyclisation pathways in the reaction between imines and enones

et al. 2016

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“…Enantioselective synthesis of N-Boc piperidines can also be realized by using two complementary approaches developed by O'Brien, Coldham, and Gawley. The first approach is by asymmetric deprotonation in the presence of (+)-sparteine surrogate that provides a more reactive complex with s-BuLi, as demonstrated by in situ IR monitoring, with respect to other chiral ligands (i.e., (−) sparteine) [41]. Alternatively, a protocol based on a dynamic thermodynamic resolution has been developed.…”

Section: Six-membered Rings: Lithiated Piperidinesmentioning

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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Asymmetric Deprotonation of N-Boc Piperidine: React IR Monitoring and Mechanistic Aspects

Abstract: The high yielding asymmetric deprotonation trapping of N-Boc piperidine is successfully realized using s-BuLi and a (+)-sparteine surrogate. Monitoring of the lithiation by in situ React IR allowed the direct observation of a prelithiation complex.

Cited by 152 publications

References 18 publications

The Mechanism of the Stereospecific Intramolecular Arylation of Lithiated Ureas: The Role of Li⁺ Probed by Electronic Structure Calculations, and by NMR and IR Spectroscopy

The Mechanism of the Stereospecific Intramolecular Arylation of Lithiated Ureas: The Role of Li⁺ Probed by Electronic Structure Calculations, and by NMR and IR Spectroscopy

Alternative tandem cyclisation pathways in the reaction between imines and enones

Nitrogen‐Bearing Lithium Compounds in Modern Synthesis

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Asymmetric Deprotonation of N-Boc Piperidine: React IR Monitoring and Mechanistic Aspects

Abstract: The high yielding asymmetric deprotonation trapping of N-Boc piperidine is successfully realized using s-BuLi and a (+)-sparteine surrogate. Monitoring of the lithiation by in situ React IR allowed the direct observation of a prelithiation complex.

Cited by 152 publications

References 18 publications

The Mechanism of the Stereospecific Intramolecular Arylation of Lithiated Ureas: The Role of Li+ Probed by Electronic Structure Calculations, and by NMR and IR Spectroscopy

The Mechanism of the Stereospecific Intramolecular Arylation of Lithiated Ureas: The Role of Li+ Probed by Electronic Structure Calculations, and by NMR and IR Spectroscopy

Alternative tandem cyclisation pathways in the reaction between imines and enones

Nitrogen‐Bearing Lithium Compounds in Modern Synthesis

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The Mechanism of the Stereospecific Intramolecular Arylation of Lithiated Ureas: The Role of Li⁺ Probed by Electronic Structure Calculations, and by NMR and IR Spectroscopy

The Mechanism of the Stereospecific Intramolecular Arylation of Lithiated Ureas: The Role of Li⁺ Probed by Electronic Structure Calculations, and by NMR and IR Spectroscopy