Synthesis of Pyrroles via Consecutive 6π-Electrocyclization/Ring-Contraction of Sulfilimines

Haut, Franz-Lucas; Feichtinger, Niklas J.; Plangger, Immanuel; Wein, Lukas Anton; Müller, Mira; Streit, Tim-Niclas; Wurst, Klaus; Podewitz, Maren; Magauer, Thomas

doi:10.1021/jacs.1c04835

Cited by 20 publications

(7 citation statements)

References 39 publications

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“…Concurrent with C–N bond formation, the Ti–C and Ti–N σ-bonding orbitals rotate perpendicular to the forming pyrrole plane and form a π back-bond with Ti. The overall transformation is similar to an aza-Nazarov cyclization. , …”

Section: Catalytic [2 + 2 + 1] Synthesis Of Pyrrolesmentioning

confidence: 82%

Ti-Catalyzed and -Mediated Oxidative Amination Reactions

Tonks

2021

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Titanium is an attractive metal for catalytic reaction development: it is earth-abundant, inexpensive, and generally nontoxic. Howeverlike most early transition metalscatalytic redox reactions with Ti are difficult because of the stability of the high-valent Ti IV state. Understanding the fundamental mechanisms behind Ti redox processes is key for making progress toward potential catalytic applications. This Account details recent progress in Ti-catalyzed (and -mediated) oxidative amination reactions that proceed through formally Ti II /Ti IV catalytic cycles. This class of reactions is built on our initial discovery of Ti-catalyzed [2 + 2 + 1] pyrrole synthesis from alkynes and azobenzene, where detailed mechanistic studies have revealed important factors that allow for catalytic turnover despite the inherent difficulty of Ti redox. Two important conclusions from mechanistic studies are that (1) low-valent Ti intermediates in catalysis can be stabilized through coordination of π-acceptor substrates or products, where they can act as "redox-noninnocent" ligands through metal-toligand π back-donation, and (2) reductive elimination processes with Ti proceed through π-type electrocyclic (or pericyclic) reaction mechanisms rather than direct σ-bond coupling.The key reactive species in Ti-catalyzed oxidative amination reactions are Ti imidos (TiNR), which can be generated from either aryl diazenes (RNNR) or organic azides (RN 3 ). These Ti imidos can then undergo [2 + 2] cycloadditions with alkynes, resulting in intermediates that can be coupled to an array of other unsaturated functional groups, including alkynes, alkenes, nitriles, and nitrosos. This basic reactivity pattern has been extended into a broad range of catalytic and stoichiometric oxidative multicomponent coupling reactions of alkynes and other reactive small molecules, leading to multicomponent syntheses of various heterocycles and aminated building blocks. For example, catalytic oxidative coupling of Ti imidos with two different alkynes leads to pyrroles, while stoichiometric oxidative coupling with alkynes and nitriles leads to pyrazoles. These heterocycle syntheses often yield substitution patterns that are complementary to those of classical condensation routes and provide access to new electron-rich, highly substituted heteroaromatic scaffolds. Furthermore, catalytic oxidative alkyne carboamination reactions can be accomplished via reaction of Ti imidos with alkynes and alkenes, yielding α,β-unsaturated imine or cyclopropylimine building blocks. New catalytic and stoichiometric oxidative amination methods such as alkyne α-diimination, isocyanide imination, and ring-opening oxidative amination of strained alkenes are continuously emerging as a result of better mechanistic understanding of Ti redox catalysis.Ultimately, these Ti-catalyzed and -mediated oxidative amination methods demonstrate the importance of examining oftencontinued...

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Section: Catalytic [2 + 2 + 1] Synthesis Of Pyrrolesmentioning

confidence: 82%

Ti-Catalyzed and -Mediated Oxidative Amination Reactions

Tonks

2021

Acc. Chem. Res.

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“… 19 , 28 The mechanistic details of the formation of V were probed by in situ NMR spectroscopy 29 − 31 using stable 13 C isotope-labeled carbonyl components: 2- 13 C-acetone and benzaldehyde-α- 13 C. Complementarily, DFT calculations were performed on the NMR-detected reaction intermediates. 32 , 33 In the following sections, the originally proposed reaction mechanism was challenged by new findings from NMR and DFT. This illustrates that even seemingly “simple” reaction mechanisms can be more complex than originally presumed.…”

Section: Introductionmentioning

confidence: 99%

“…Potential applications in pharmaceutical chemistry and in materials science are known for other 1,2,4-triazoline derivatives , and especially for their oxidized 1,2,4-triazole congeners. − To establish a starting point for future synthetic explorations, the initially proposed reaction mechanism (Scheme B) for the formation of compounds of type V was tested by a combined NMR/density functional theory (DFT) approach. Furthermore, we were interested in a better understanding of the observed side reaction of educts IV leading to a metathetical carbonyl exchange, which was recently termed as transazination or transalkylidation. , The mechanistic details of the formation of V were probed by in situ NMR spectroscopy − using stable 13 C isotope-labeled carbonyl components: 2- 13 C-acetone and benzaldehyde-α- 13 C. Complementarily, DFT calculations were performed on the NMR-detected reaction intermediates. , In the following sections, the originally proposed reaction mechanism was challenged by new findings from NMR and DFT. This illustrates that even seemingly “simple” reaction mechanisms can be more complex than originally presumed.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Insights into the Formation of 1-Alkylidene/Arylidene-1,2,4-triazolinium Salts: A Combined NMR/Density Functional Theory Approach

et al. 2022

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In a recent report on the synthetic approach to the novel substance class of 1-alkylidene/arylidene-1,2,4-triazolinium salts, a reaction mechanism suggesting a regioselective outcome was proposed. This hypothesis was tested via a combined NMR and density functional theory (DFT) approach. To this end, three experiments with 13 C-labeled carbonyl reactants were monitored in situ by solution-state NMR. In one experiment, an intermediate as described in the former mechanistic proposal was observed. However, incorporation of 13 C isotope labels into multiple sites of the heterocycle could not be reconciled with the “regioselective mechanism”. It was found that an unproductive reaction pathway can lead to 13 C scrambling, along with metathetical carbonyl exchange. According to DFT calculations, the concurring reaction pathways are connected via a thermodynamically controlled cyclic 1,3-oxazetidine intermediate. The obtained insights were applied in a synthetic study including aliphatic ketones and para-substituted benzaldehydes. The mechanistic peculiarities set the potential synthetic scope of the novel reaction type.

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“…Here, comparison to its predecessor 5an reveals the effective replacement of the methyl substituent with a phenyl. Finally, if indole 5ao is subjected to nitrogen insertion through a precedented N-amination and oxidative aromatization sequence, cinnoline 7ao can be accessed, now the formal C-to-N exchange product of starting quinoline 4ao (39)(40)(41). This work offers a broadly applicable, C2selective, net carbon deletion of quinolines and related azaarenes through a ring contraction of the corresponding N-oxides.…”

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confidence: 99%

Scaffold hopping by net photochemical carbon deletion of azaarenes

Woo

Christian

Burgess

et al. 2022

Science

128

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Discovery chemists routinely identify purpose-tailored molecules through an iterative structural optimization approach, but the preparation of each successive candidate in a compound series can rarely be conducted in a manner matching their thought process. This is because many of the necessary chemical transformations required to modify compound cores in a straightforward fashion are not applicable in complex contexts. We report a method that addresses one facet of this problem by allowing chemists to hop directly between chemically distinct heteroaromatic scaffolds. Specifically, we show that selective photolysis of quinoline N -oxides with 390-nanometer light followed by acid-promoted rearrangement affords N -acylindoles while showing broad compatibility with medicinally relevant functionality. Applications to late-stage skeletal modification of compounds of pharmaceutical interest and more complex transformations involving serial single-atom changes are demonstrated.

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Synthesis of Pyrroles via Consecutive 6π-Electrocyclization/Ring-Contraction of Sulfilimines

Cited by 20 publications

References 39 publications

Ti-Catalyzed and -Mediated Oxidative Amination Reactions

Ti-Catalyzed and -Mediated Oxidative Amination Reactions

Mechanistic Insights into the Formation of 1-Alkylidene/Arylidene-1,2,4-triazolinium Salts: A Combined NMR/Density Functional Theory Approach

Scaffold hopping by net photochemical carbon deletion of azaarenes

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