Recent Advances in Charge-Accelerated Aza-Claisen Rearrangements

Nubbemeyer, U.

doi:10.1007/b96891

Cited by 73 publications

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“…[3,4] The basic nitrogen atom provides the site for charge acceleration, usually through protonation, quaternization, or Lewis acid coordination. Even so, simple allylaniline aza-Claisen reactions require stoichiometric amounts of Lewis acids such as BF 3 .OEt 2 and reaction temperatures well in excess of 100 8C (Scheme 1). [5] Our interest in aryne chemistry [6] led us to speculate that the addition of benzyne to a tertiary allylamine could set up an aza-Claisen rearrangement pathway, thus creating a novel route to functionalized anilines.…”

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The Benzyne Aza‐Claisen Reaction

et al. 2009

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The Benzyne Aza‐Claisen Reaction

et al. 2009

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“…After deprotonation, methylchloroformate was added to activate the alkyne function towards the 5 ‐exo attack of the nitrogen atom, which enabled indole 4 d to be obtained in 63 % yield (Scheme 4). Presumably, intramolecular Michael addition to the triple bond generates an allenolate system that can undergo [3,3] sigmatropic rearrangement 14c. Final proton exchange yields 4 d .…”

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confidence: 99%

From PtCl₂‐ and Acid‐Catalyzed to Uncatalyzed Cycloisomerization of 2‐Propargyl Anilines: Access to Functionalized Indoles

et al. 2007

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Indoles are ubiquitous motifs in pharmaceuticals as well as in important natural products. New and straightforward methods to access these substrates are thus always highly desirable. [1] In this context, the metal-catalyzed cycloisomerization of polyunsaturated precursors is an ideal process to be explored. One of the main strategies has consisted of a 5-endo-dig metal-catalyzed [2,3] cyclization of acetylenic derivatives (Scheme 1). Ortho-Halogenoanilines constitute valuable starting materials for the synthesis of substrates 1 and can even be used to generate in situ the akynylaryl species by a Sonogashira-type coupling reaction prior to cyclization.[2d] A recent variant based on imines has also been reported. [4] To the best of our knowledge, the alternative 5-exo-dig isomerization approach from precursors 2 has received much less attention, [5] and we decided to examine this potentially new route.Platinum(II)-based catalysis has recently witnessed a tremendous development which has led to new synthetic methods [6] as well as versatile applications in the total synthesis [7] of natural products and asymmetric catalysis.[8]Recently, we reported on the use of allenyne and enynamide partners, [9] and showed that the substituent at the propargylic position had a dramatic influence on the course of the PtCl 2 -catalyzed cycloisomerization of various enyne systems.[10] To examine the scope of the reaction and to generate diverse platforms we have thus investigated flexible propargylic precursors of type 3 [11,12] (Scheme 1) on which we can easily vary the oxygen, nitrogen, and alkyne substituents (X, R 1 , and R 2 ).Our initial studies involving substrate 3 a (Scheme 2, Eq. (1) were highly encouraging, and enabled indole 4 a to be isolated in 91 % yield. We next examined more challenging precursors. Gratifyingly, N,N-diallyl precursor 3 b also underwent the transformation [Scheme 2, Eq. (2)]. In this case, an additional transfer of an allyl group from the nitrogen to the terminal alkyne carbon atom occurred (Scheme 2, entry 1). This formally constitutes an aminoallylation of the triple bond followed by an isomerization of the unsaturated bond. An analogous allyl transfer has been previously described by Fürstner et al. in the synthesis of furan derivatives. However, in this case, stabilization of the vinyl-metal intermediate via an enolate species seems necessary since only acetylenic Scheme 1. Transition-metal-catalyzed formation of indoles from o-alkynylanilines and o-propargylanilines. M = metal.Scheme 2. Indole formation and allyl transfer.

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“…Cope-type rearrangements constitute a highly efficient means for carbon–carbon bond formation, offering high regio- and stereocontrol which renders them especially useful in synthesis [1]. The Aza-Cope rearrangement in particular has some advantages over its oxo-counterpart, namely the fine tuning of the reaction temperature which can be achieved by attaching different substituents to the nitrogen of the rearranging system [2-5], by adding charges or by encapsulating it [6].…”

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N-heteroatom substitution effect in 3-aza-cope rearrangements

Gomes

Pinto

Glória

et al. 2013

Chemistry Central Journal

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BackgroundThe nature of the heteroatom substitution in the nitrogen of a 3-aza-Cope system is explored.ResultsWhile N-propargyl isoxazolin-5-ones suffer 3-aza-Cope rearrangements at 60°C, the corresponding N-propargyl pyrazol-5-ones need a higher temperature of 180°C for the equivalent reaction. When the propargyl group is substituted by an allyl group, the temperature of the rearrangement for both type of compounds is less affected by the nature of the heteroatom present. Treatment with a base, such as ethoxide, facilitates the rearrangement, and in the case of isoxazol-5- ones other ring opening reactions take precedence, involving N–O ring cleavage of the 5-membered ring. However when base-catalysed decomposition is prevented by substituents, products arising from a room temperature aza-Cope rearrangement are isolated. A possible mechanistic pathway based on free energies derived from density functional calculations involving cyclic intermediates is proposed.ConclusionsThe nature of the heteroatom substitution in the nitrogen of a 3-aza-Cope system leads to a remarkable difference in the energy of activation of the reaction.

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Recent Advances in Charge-Accelerated Aza-Claisen Rearrangements

Cited by 73 publications

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The Benzyne Aza‐Claisen Reaction

The Benzyne Aza‐Claisen Reaction

From PtCl₂‐ and Acid‐Catalyzed to Uncatalyzed Cycloisomerization of 2‐Propargyl Anilines: Access to Functionalized Indoles

N-heteroatom substitution effect in 3-aza-cope rearrangements

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Recent Advances in Charge-Accelerated Aza-Claisen Rearrangements

Cited by 73 publications

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The Benzyne Aza‐Claisen Reaction

The Benzyne Aza‐Claisen Reaction

From PtCl2‐ and Acid‐Catalyzed to Uncatalyzed Cycloisomerization of 2‐Propargyl Anilines: Access to Functionalized Indoles

N-heteroatom substitution effect in 3-aza-cope rearrangements

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From PtCl₂‐ and Acid‐Catalyzed to Uncatalyzed Cycloisomerization of 2‐Propargyl Anilines: Access to Functionalized Indoles