Optimizing Amine‐Mediated Alkyne–Allene Isomerization to Improve Benzannulation Cascades: Synergy between Theory and Experiments

Gomes, Gabriel; Morrison, Alec E.; Dudley, Gregory B.; Alabugin, Igor V.

doi:10.1002/ejoc.201801052

Cited by 22 publications

(12 citation statements)

References 68 publications

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“…[2] The densely packed arrangemento ff unctional groups on thea romatic ring in these molecules is often associated with their function, but also has implications for their synthesis. Notwithstanding the many useful methods that have accruedf or arene functionalization [3] and ring construction, [4] installing each substituent in its precise location requires careful consideration of both regiocontrol and functionalg roup compatibility over severals ynthetic steps, and general methods are lacking. Consequently 1,2,3,4-substituted benzenoids are underrepresented in pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

Regioselective Synthesis of 1,2,3,4‐Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts**

Nilova

Sibbald

Valente

et al. 2021

Chemistry A European J

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Herein, the synthesis of 1,2,3,4-tetrasubstituted benzenoid rings, motifs found in pharmaceutical,a grochemical, and natural products, is described. [1] In the past, the regioselective syntheses of such compounds have been as ignificant challenge. This work reports am ethod using substituted arynesd erived from aryl(Mes)iodonium salts to access ar ange of densely functionalized 1,2,3,4-tetrasubstituted benzenoid rings. Significantly, it was found that halide substituents are compatible under these conditions, enabling post-synthetic elaboration via palladium-catalyzed coupling. This concise strategy is predicated on two regioselective events:1 )ortho-d eprotonation of aryl(Mes)iodonium salts to generate as ubstituted aryne intermediate, and 2) regioselective trapping of said arynes, thereby improving previously reportedr eaction conditions to generatea rynes at room temperature and in shorter reaction times. Density functional theory (DFT) computations and linear free energy relationship (LFER) analysis suggest the regioselectivity of deprotonation is influenced by both proximal and distal ring substituents on the aryne precursor.Ac ompetition experiment furtherr eveals the role of arene substituents on relative reactivity of aryl(Mes)iodoniums as aryne precursors.Scheme1.Selectedexamples and retrosynthesis of 1,2,3,4-substituted benzenoid rings.

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Section: Introductionmentioning

confidence: 99%

Regioselective Synthesis of 1,2,3,4‐Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts**

Nilova

Sibbald

Valente

et al. 2021

Chemistry A European J

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“…Without metal catalyst to activate dioxygen, in this reaction, carbanion should be formed via α‐proton abstraction with the help of basic catalyst, then readily reacts with dioxygen. Several groups have reported the excellent ability of TBD for proton abstracting, [11b–e, 18–20] and the doubly proton transfer mechanism was also proposed. With much effort, we observed the interaction between ketone and TBD in use of NMR, then kinetic experiments and theoretical calculations were carried out to investigate the rate‐determining step.…”

Section: Resultsmentioning

confidence: 99%

“…As a result, the TBD‐enhanced activity of peroxide allowed its reaction with DMSO. Though the double proton transfer has been reported in TBD‐catalyzed reactions, [12, 19] to the best of our knowledge, its application on enhancing the reactivity of peroxide has not been uncovered yet.…”

Section: Resultsmentioning

confidence: 99%

1,5,7‐Triazabicyclo[4.4.0]dec‐5‐ene Enhances Activity of Peroxide Intermediates in Phosphine‐Free α‐Hydroxylation of Ketones

et al. 2021

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The critical role of double hydrogen bonds was addressed for the aerobic α‐hydroxylation of ketones catalyzed by 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD), in the absence of either a metal catalyst or phosphine reductant. Experimental and theoretical investigations were performed to study the mechanism. In addition to initiating the reaction by proton abstraction, a more important role of TBD was revealed, that is, to enhance the oxidizing ability of peroxide intermediates, allowing DMSO to be used rather than commonly used phosphine reductants. Further characterizations with nuclear Overhauser effect spectroscopy (NOESY) confirmed the presence of double hydrogen bonds between TBD and the ketone, and kinetic studies suggested the attack of dioxygen on the TBD‐enol adduct to be the rate‐determining step. This work should encourage the application of TBD as a catalyst for oxidations.

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“…In the first case, the N-H bond on the catalyst is stretched to obtain the isomerization, and the reaction pathway and transition structure are near identical to those obtained by traditional means. 50 The oxidative addition of Pd in Figure 2g is readily found by increasing the Ph-Cl bond distance, showing that imposed activation can be applied to organometallic reactions using extended density-functional tight-binding theory. 51…”

Section: The Dieckmann Condensation 47 Inmentioning

confidence: 94%

Automatic discovery of chemical reactions using imposed activation

Lavigne

Gomes²,

Pollice³

et al. 2020

Preprint

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Computational power and quantum chemical methods have improved immensely since computers were first applied to the study of reactivity, but the de novo prediction of chemical reactions has remained challenging. We show that complex reactions can be efficiently and autonomously predicted using chemical activation imposed by simple geometrical constraints. Our approach is demonstrated on realistic and challenging chemistry, such as a triple cyclization cascade involved in the total synthesis of a natural product and several oxidative addition reactions of complex drug-like molecules. Notably and in contrast with traditional hand-guided computational chemistry calculations, our method requires minimal human involvement and no prior knowledge of products or mechanisms. Imposed activation can be a transformational tool to screen for chemical reactivity and mechanisms as well as to study byproduct formation and decomposition.<br>

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Optimizing Amine‐Mediated Alkyne–Allene Isomerization to Improve Benzannulation Cascades: Synergy between Theory and Experiments

Cited by 22 publications

References 68 publications

Regioselective Synthesis of 1,2,3,4‐Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts**

Regioselective Synthesis of 1,2,3,4‐Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts**

1,5,7‐Triazabicyclo[4.4.0]dec‐5‐ene Enhances Activity of Peroxide Intermediates in Phosphine‐Free α‐Hydroxylation of Ketones

Automatic discovery of chemical reactions using imposed activation

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