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Publications | The Nairoukh Research Group

Publications

2024
Agbaria, M. ; Egbaria, N. ; Nairoukh, Z. . Unveiling Novel Synthetic Pathways Through Brook Rearrangement. Synthesis 2024. Publisher's VersionAbstract

The Brook rearrangement is a valuable synthetic tool that facilitates the controlled construction of complex molecules. Conventionally, it generates carbanion intermediates utilized in subsequent functionalization reactions. In this Review, we will explore recent advancements in the Brook rearrangement that extend beyond the traditional functionalization reactions. Specifically, we will highlight its involvement in unusual bonds cleavage, annulation reactions, and dearomatization efforts. The novelty of this rearrangement is underscored by showcasing its most recent applications.

2023
Amit, E. ; Berg, I. ; Zhang, W. ; Mondal, R. ; Shema, H. ; Gutkin, V. ; Kravchuk, T. ; Toste, F. D. ; Nairoukh, Z. ; Gross, E. . Selective Deposition Of N-Heterocyclic Carbene Monolayers On Designated Au Microelectrodes Within An Electrode Array. Small 2023.
Hu, M. ; Ding, H. ; Desnoo, W. ; Tantillo, D. J. ; Nairoukh, Z. . The Construction Of Highly Substituted Piperidines Via Dearomative Functionalization Reaction. Angew. Chem. Int. Ed. 2023, e202315108. Publisher's VersionAbstract

Nitrogen heterocycles play a vital role in pharmaceuticals and natural products, with the six-membered aromatic and aliphatic architectures being commonly used. While synthetic methods for aromatic N-heterocycles are well-established, the synthesis of their aliphatic functionalized analogues, particularly piperidine derivatives, poses a significant challenge. In that regard, we propose a stepwise dearomative functionalization reaction for the construction of highly decorated piperidine derivatives with diverse functional handles. We also discuss challenges related to site-selectivity, regio- and diastereoselectivity, and provide insights into the reaction mechanism through mechanistic studies and density functional theory computations. 

Mondal, R. ; Agbaria, M. ; Cohen, O. ; Nairoukh, Z. . Brook Rearrangement As Trigger For Dearomatization Reaction: Synthesis Of Non-Aromatic N-Heterocycles. Chem. Eur. J. 2023. Publisher's VersionAbstract

The [1,2]-Brook rearrangement stands as a potent technique for constructing complex molecules. In this study, we showcase its power in the dearomatization of aromatic N-heterocycles. Through a concise four-step process that integrates lithiation, nucleophilic addition, Brook rearrangement and dearomatization reaction, we demonstrate a versatile strategy for generating diverse non-aromatic N-heterocycles with functional capabilities. Various acyl silanes, halo-pyridines, and quinolines have been explored within this context.

2021
Mondal, R. ; Agbaria, M. ; Nairoukh, Z. . Fluorinated Rings: Conformation And Application. Chem. Eur. J. 2021, DOI: 10.1002/chem.202005425 2021. Publisher's VersionAbstract

The introduction of fluorine atoms into molecules and materials across many fields of academic and industrial research is now commonplace, owing to their unique properties and effects. A particularly interesting feature of fluorine substitution is its impact on the relative orientation of a C?F bond when incorporated with organic molecules. In this Review, we will be shining light on this unique feature by discussing the conformational behaviour of aliphatic carbo- and heterocyclic systems. The conformational preference of each system is associated with various interactions introduced by fluorine substitution such as charge-dipole interactions, dipole-dipole interactions and hyperconjugative interactions. The contribution of each interaction on the stabilization of the fluorinated alicyclic system, which manifests itself in low conformations, will be discussed in details. The novelty of this feature will be demonstrated by presenting the most recent applications.

2020
Wagener, T. ; Heusler, A. ; Nairoukh, Z. ; Bergander, K. ; Daniliuc, C. G. ; Glorius, F. . Accessing (Multi)Fluorinated Piperidines Using Heterogeneous Hydrogenation. ACS Catal. 2020, 10, 12052 – 12057. Publisher's VersionAbstract
Fluorinated piperidines are desirable motifs for pharmaceutical and agrochemical research. Nevertheless, general synthetic access remains out of reach. Herein, we describe a simple and robust cis-selective hydrogenation of abundant and cheap fluoropyridines to yield a broad scope of (multi)fluorinated piperidines. This protocol enables the chemoselective reduction of fluoropyridines while tolerating other (hetero)aromatic systems using a commercially available heterogenous catalyst. Fluorinated derivatives of important drug compounds are prepared, and a straightforward strategy for the synthesis of enantioenriched fluorinated piperidines is disclosed.
Gelis, C. ; Heusler, A. ; Nairoukh, Z. ; Glorius, F. . Catalytic Transfer Hydrogenation Of Arenes And Heteroarenes. Chem. Eur. J. 2020, 26, 14090 – 14094. Publisher's VersionAbstract
Abstract Transfer hydrogenation reactions are of great interest to reduce diverse molecules under mild reaction conditions. To date, this type of reaction has only been successfully applied to alkenes, alkynes and polarized unsaturated compounds such as ketones, imines, pyridines, etc. The reduction of benzene derivatives by transfer hydrogenation has never been described, which is likely due to the high energy barrier required to dearomatize these compounds. In this context, we have developed a catalytic transfer hydrogenation reaction for the reduction of benzene derivatives and heteroarenes to form complex 3-dimensional scaffolds bearing various functional groups at room temperature without needing compressed hydrogen gas.
Nairoukh, Z. ; Strieth-Kalthoff, F. ; Bergander, K. ; Glorius, F. . Understanding The Conformational Behavior Of Fluorinated Piperidines: The Origin Of The Axial-F Preference. Chem. Eur. J. 2020, 26, 6141 – 6146. Publisher's VersionAbstract
Abstract Gaining an understanding of the conformational behavior of fluorinated compounds would allow for expansion of the current molecular design toolbox. In order to facilitate drug discovery efforts, a systematic survey of a series of diversely substituted and protected fluorinated piperidine derivatives has been carried out using NMR spectroscopy. Computational investigations reveal that, in addition to established delocalization forces such as charge?dipole interactions and hyperconjugation, solvation and solvent polarity play a major role. This work codifies a new design principle for conformationally rigid molecular scaffolds.
2019
Wiesenfeldt, M. P. ; Nairoukh, Z. ; Glorius, F. . Chemoselektive Katalytische Hydrierung Flourierter Aromatenchemoselektive Katalytische Hydrierung Flourierter Aromaten, 2019.
Nairoukh, Z. ; Schlepphorst, C. ; Glorius, F. . Verfahren Zur Herstellung Fluorierten Heterocyclischen Aliphatischer Verbindungen, 2019. Publisher's Version
Wiesenfeldt, M. P. ; Nairoukh, Z. ; Dalton, T. ; Glorius, F. . Selective Arene Hydrogenation For Direct Access To Saturated Carbo- And Heterocycles. Angew. Chem. Int. Ed. 2019, 58, 10460 – 10476 2019. Publisher's VersionAbstract
Abstract Arene hydrogenation provides direct access to saturated carbo- and heterocycles and thus its strategic application may be used to shorten synthetic routes. This powerful transformation is widely applied in industry and is expected to facilitate major breakthroughs in the applied sciences. The ability to overcome aromaticity while controlling diastereo-, enantio-, and chemoselectivity is central to the use of hydrogenation in the preparation of complex molecules. In general, the hydrogenation of multisubstituted arenes yields predominantly the cis isomer. Enantiocontrol is imparted by chiral auxiliaries, Br?nsted acids, or transition-metal catalysts. Recent studies have demonstrated that highly chemoselective transformations are possible. Such methods and the underlying strategies are reviewed herein, with an emphasis on synthetically useful examples that employ readily available catalysts.
Nairoukh, Z. ; Wollenburg, M. ; Schlepphorst, C. ; Bergander, K. ; Glorius, F. . The Formation Of All-Cis-(Multi)Fluorinated Piperidines By A Dearomatization&Ndash;Hydrogenation Process. Nat. Chem. 2019, 11, 264 – 270 2019. Publisher's VersionAbstract
Piperidines and fluorine substituents are both independently indispensable components in pharmaceuticals, agrochemicals and materials. Logically, the incorporation of fluorine atoms into piperidine scaffolds is therefore an area of tremendous potential. However, synthetic approaches towards the formation of these architectures are often impractical. The diastereoselective synthesis of substituted monofluorinated piperidines often requires substrates with pre-defined stereochemistry. That of multifluorinated piperidines is even more challenging, and often needs to be carried out in multistep syntheses. In this report, we describe a straightforward process for the one-pot rhodium-catalysed dearomatization–hydrogenation of fluoropyridine precursors. This strategy enables the formation of a plethora of substituted all-cis-(multi)fluorinated piperidines in a highly diastereoselective fashion through pyridine dearomatization followed by complete saturation of the resulting intermediates by hydrogenation. Fluorinated piperidines with defined axial/equatorial orientation of fluorine substituents were successfully applied in the preparation of commercial drugs analogues. Additionally, fluorinated PipPhos as well as fluorinated ionic liquids were obtained by this dearomatization–hydrogenation process.
2018
Wiesenfeldt, M. P. ; Nairoukh, Z. ; Glorius, F. . Verfahren Zur Herstellung Fluorierter Cyclischer Aliphatischer Verbindungen, 2018. Publisher's Version
Huang, J. Q. ; Nairoukh, Z. ; Marek, I. . Electrophilic Fluorination Of Stereodefined Disubstituted Silyl Ketene Hemiaminals En Route To Tertiary Α-Fluorinated Carbonyl Derivatives. Org. Biomol. Chem. 2018, 16, 1079 – 1082 2018. Publisher's VersionAbstract
A highly diastereoselective synthesis of tertiary α-fluoro carbonyl compounds is reported in only two chemical steps from a simple alkyne through the reaction of stereodefined fully substituted silyl ketene hemiaminal derivatives with Selectfluor.
Huang, J. Q. ; Nairoukh, Z. ; Marek, I. . Electrophilic Oxidation Of Stereodefined Polysubstituted Silyl Ketone Aminals. Eur. J. Org. Chem. 2018, 614 – 618 2018. Publisher's VersionAbstract
We reported herein a practical approach to acyclic tertiary α-hydroxy carbonyl compounds in only two chemical steps from alkynes with excellent diastereoselectivity through the oxidation of stereodefined polysubstituted silyl ketone aminals. The products could be smoothly converted to synthetically useful enantiomerically enriched 1,2-diol derivatives.
2017
Wiesenfeldt, M. P. ; Nairoukh, Z. ; Li, W. ; Glorius, F. . Hydrogenation Of Fluoroarenes: Direct Access To All-Cis-(Multi)Fluorinated Cycloalkanes. Science 2017, 357, 908 – 912 2017. Publisher's VersionAbstract
Carbon-fluorine bonds are highly polarized, and this effect is magnified when several of them reside on the same face of a saturated ring. However, most existing fluorination methods have difficulty consistently producing this all-cis mutual configuration. Wiesenfeldt et al. used a rhodium catalyst in nonpolar solvent to add hydrogens selectively to just one face of a wide variety of flat fluoroarene rings, pushing all fluorines toward the other face. The reaction also pushed fluorine toward the same face as nitrogen and oxygen in heterocycles such as indole and benzofuran.Science, this issue p. 908All-cis-multifluorinated cycloalkanes exhibit intriguing electronic properties. In particular, they display extremely high dipole moments perpendicular to the aliphatic ring, making them highly desired motifs in material science. Very few such motifs have been prepared, as their syntheses require multistep sequences from diastereoselectively prefunctionalized precursors. Herein we report a synthetic strategy to access these valuable materials via the rhodium–cyclic (alkyl)(amino)carbene (CAAC)–catalyzed hydrogenation of readily available fluorinated arenes in hexane. This route enables the scalable single-step preparation of an abundance of multisubstituted and multifluorinated cycloalkanes, including all-cis-1,2,3,4,5,6-hexafluorocyclohexane as well as cis-configured fluorinated aliphatic heterocycles.
Nairoukh, Z. ; Cormier, M. ; Marek, I. . Merging C&Ndash;H And C&Ndash;C Bond Cleavage In Organic Synthesis. Nat. Rev. Chem. 2017, 1, 0035 2017. Publisher's VersionAbstract
Metal-catalysed functionalization of a carbon–hydrogen bond can occur selectively even in the presence of ostensibly more reactive functional groups. Such conversions have changed our perceptions of organic chemistry because we can now consider a C–H bond as a functional group, the reactions of which are among the most attractive and powerful means to rapidly add complexity. Another versatile tool in organic synthesis is the metal-catalysed selective cleavage of C–C bonds. Applying both expedient methods in a tandem process would give us an ideal approach to synthesizing complex molecular architectures. The challenge lies in ensuring that the reactions do not interfere with each other; the simultaneous control of both C–H and C–C bond activations is the subject of this Review. The reactions that meet this challenge and enable a selective merger of C–H and C–C bond activations in a one-pot process are discussed. Their realization could afford sophisticated molecular fragments that are otherwise difficult to access.
Nairoukh, Z. ; Kumar, G. G. K. S. N. ; Minko, Y. ; Marek, I. . Enantioselective Allylic Alkylation Of Stereodefined Polysubstituted Copper Enolates As An Entry To Acyclic Quaternary Carbon Stereocentres. Chem. Sci. 2017, 8, 627 – 630 2017. Publisher's VersionAbstract
A sequence of regio- and stereoselective carbometalation followed by oxidation of ynamides leads to stereodefined fully substituted enolates that subsequently react with various functionalized allyl bromide reagents to provide the expected products possessing an enantiomerically pure quaternary carbon stereocentre in the α-position to the carbonyl group in excellent yields and enantiomeric ratios after cleavage of the oxazolidinone moiety. Three new bonds are formed in a single-pot operation.
2016
Haimov, E. ; Nairoukh, Z. ; Shterenberg, A. ; Berkovitz, T. ; Jamison, T. F. ; Marek, I. . Stereoselective Formation Of Fully Substituted Ketone Enolates. Angew. Chem. Int. Ed. 2016, 55, 5517 – 5520 2016. Publisher's VersionAbstract
Abstract The application of stereochemically defined acyclic fully substituted enolates of ketones to the enantioselective synthesis of quaternary carbon stereocenters would be highly valuable. Herein, we describe an approach leading to the formation of several new stereogenic centers through a combined metalation?addition of a carbonyl?carbamoyl transfer to reveal in?situ stereodefined α,α-disubstituted enolates of ketone as a single stereoisomer. This approach could produce a series of aldol and Mannich products from enol carbamate with excellent diastereomeric ratios.