Rajarshi Mondal, Mohamed Agbaria, and Zackaria Nairoukh. 2021. “Fluorinated Rings: Conformation and Application.” Chem. Eur. J. 2021, DOI: 10.1002/chem.202005425. Publisher's Version Abstract

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.

Tobias Wagener, Arne Heusler, Zackaria Nairoukh, Klaus Bergander, Constantin G. Daniliuc, and Frank Glorius. 2020. “Accessing (Multi)Fluorinated Piperidines Using Heterogeneous Hydrogenation.” ACS Catal. 2020, 10, 12052 – 12057. Publisher's Version Abstract
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.
Coralie Gelis, Arne Heusler, Zackaria Nairoukh, and Frank Glorius. 2020. “Catalytic Transfer Hydrogenation of Arenes and Heteroarenes.” Chem. Eur. J. 2020, 26, 14090 – 14094. Publisher's Version Abstract
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.
Zackaria Nairoukh, Felix Strieth-Kalthoff, Klaus Bergander, and Frank Glorius. 2020. “Understanding the Conformational Behavior of Fluorinated Piperidines: The Origin of the Axial-F Preference.” Chem. Eur. J. 2020, 26, 6141 – 6146. Publisher's Version Abstract
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.
Zackaria Nairoukh, Marco Wollenburg, Christoph Schlepphorst, Klaus Bergander, and Frank Glorius. 2019. “The Formation of All-cis-(multi)fluorinated Piperidines by a Dearomatization–Hydrogenation Process.” Nat. Chem. 2019, 11, 264 – 270. Publisher's Version Abstract
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.
Mario P. Wiesenfeldt, Zackaria Nairoukh, Toryn Dalton, and Frank Glorius. 2019. “Selective Arene Hydrogenation for Direct Access to Saturated Carbo- and Heterocycles.” Angew. Chem. Int. Ed. 2019, 58, 10460 – 10476. Publisher's Version Abstract
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.
Jian Qiang Huang, Zackaria Nairoukh, and Ilan Marek. 2018. “Electrophilic Fluorination of Stereodefined Disubstituted Silyl Ketene Hemiaminals en route to Tertiary α-Fluorinated Carbonyl Derivatives.” Org. Biomol. Chem. 2018, 16, 1079 – 1082. Publisher's Version Abstract
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.
Jian Qiang Huang, Zackaria Nairoukh, and Ilan Marek. 2018. “Electrophilic Oxidation of Stereodefined Polysubstituted Silyl Ketone Aminals.” Eur. J. Org. Chem. 2018, 614 – 618. Publisher's Version Abstract
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.
Zackaria Nairoukh, Gunda G. K. S. Narayana Kumar, Yury Minko, and Ilan Marek. 2017. “Enantioselective Allylic Alkylation of Stereodefined Polysubstituted Copper Enolates as an Entry to Acyclic Quaternary Carbon Stereocentres.” Chem. Sci. 2017, 8, 627 – 630. Publisher's Version Abstract
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.
Mario P. Wiesenfeldt, Zackaria Nairoukh, Wei Li, and Frank Glorius. 2017. “Hydrogenation of Fluoroarenes: Direct Access to All-cis-(multi)fluorinated Cycloalkanes.” Science 2017, 357, 908 – 912. Publisher's Version Abstract
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.
Zackaria Nairoukh, Morgan Cormier, and Ilan Marek. 2017. “Merging C–H and C–C Bond Cleavage in Organic Synthesis.” Nat. Rev. Chem. 2017, 1, 0035. Publisher's Version Abstract
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.
Elvira Haimov, Zackaria Nairoukh, Alexander Shterenberg, Tiran Berkovitz, Timothy F. Jamison, and Ilan Marek. 2016. “Stereoselective Formation of Fully Substituted Ketone Enolates.” Angew. Chem. Int. Ed. 2016, 55, 5517 – 5520. Publisher's Version Abstract
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.
Abstract The regio- and stereoselective formation of stereodefined polysubstituted silyl ketene aminals is easily achieved through selective combined carbometalation?oxidation?silylation reactions. These substrates are ideal candidates for Mukaiyama aldol reactions with aliphatic aldehydes as they give the aldol products with a quaternary carbon stereocenter α to the carbonyl groups in outstanding diastereoselectivities.
Monzer Fanun, Ahmad Shakarnah, Michael Schwarze, Reinhard Schomäcker, Zackaria Nairoukh, and Jochanan Blum. 2014. “Characterization of Water/n-Propanol/Nonionic Surfactant/ Phenylacetylene Microemulsions.” Eur. Chem. Bull. 2014, 3, 81 – 84.
Monzer Fanun, Ahmad Shakarnah, Michael Schwarze, Reinhard Schomäcker, Zackaria Nairoukh, and Jochanan Blum. 2014. “Properties of Water/n-Propanol/Ionic Surfactant/ Phenylacetylene Micellar Systems.” Eur. Chem. Bull. 2014, 3, 426 – 429.
Zackaria Nairoukh, Monzer Fanun, Michael Schwarze, Reinhard Schomäcker, and Jochanan Blum. 2014. “Cyclotrimerization of Alkynes vs. Ketone Formation in Aqueous Microemulsion.” J. Mol. Catal. A Chem. 2014, 382, 93 – 98. Publisher's Version Abstract
In the course of our attempts to develop sustainable conditions for the catalytic organic reactions by replacement of the traditional but environmentally disfavored organic solvents by water, we studied the cyclotrimerizations of alkynes, in aqueous microemulsions. The catalyst for these reactions was the rhodium-trichloride encaged within silica sol–gel. In acidic aqueous media, alkynes can undergo addition of water to form their corresponding ketones. In order to eliminate completely the formation of ketones, relatively low reaction temperatures are required. At higher reaction temperatures, however, buffered microemulsion media is preferable. Cyclotrimerization of alkynes proved to be dependent on the reaction temperatures, the electronic nature of the substrates, the electronic nature of the surfactant and on the hydrophobicity of the sol–gel support. During the cyclotrimerization reaction, the rhodium complex was turned to Rh(0) nanoparticles characterized by TEM measurements. These investigations may be regarded as model studies for the conversion of alkynes into substituted benzenes in water.
I. Volovych, Y. Kasaka, M. Schwarze, Z. Nairoukh, J. Blum, M. Fanun, D. Avnir, and R. Schomäcker. 2014. “Investigation of Sol–Gel Supported Palladium Catalysts for Heck Coupling Reactions in o/w-Microemulsions.” J. Mol. Catal. A Chem. 2014, 393, 210 – 221. Publisher's Version Abstract
Sol–gel supported palladium catalysts are investigated for the Heck coupling reaction between styrene and iodo-/bromobenzene to trans-stilbenes in o/w-microemulsions as alternative reaction medium. High conversions and selectivities are obtained with these catalysts and they show better catalytic performance than their commercial analogs Pd@SiO2 or Pd/C. The influence of the catalyst structure on the activity is investigated in detail showing mass transport limitations that can be optimized by the palladium loading. The catalyst is recyclable >6 times with negligible palladium leaching into the solution. Because of the good recyclability under retention of activity and selectivity, the influence of transport limitations is suppressed and the total catalyst efficiency is increased to more than 2.
Zackaria Nairoukh and Jochanan Blum. 2014. “Regioselective Hydroaminomethylation of Vinylarenes by a Sol–Gel Immobilized Rhodium Catalyst.” J. Org. Chem. 2014, 79, 2397 – 2403. Publisher's Version Abstract
In the course of our studies toward the development of new heterogeneous conditions for better controlling regioselectivity in organic reactions, we investigated the application of sol–gel immobilized organometallic catalyst for regioselective hydroaminomethylation of vinylarenes with aniline or nitroarene derivatives in an aqueous microemulsion. By immobilization of 6 mol % [Rh(cod)Cl]2 within a hydrophobic silica sol–gel matrix we were able to perform efficient hydroaminomethylation under mild conditions and isolate 2-arylpropylamines with high regioselectivity. The regioselectivity of the reaction was found to be mainly dependent on the hydrophobicity of the catalyst support. It is also significantly affected by the electronic nature of the substrates, by the reaction temperature, and by syngas pressure. The heterogenized catalyst can be reused for several times.
I. Volovych, M. Schwarze, Z. Nairoukh, J. Blum, M. Fanun, and R. Schomäcker. 2014. “Sol-Gel Immobilized Catalyst Systems for Tandem Transformations with trans-Stilbene as an Intermediate.” Catal. Commun. 2014, 53, 1 – 4. Publisher's Version Abstract
Tandem catalytic systems containing one or two sol-gel immobilized catalysts were successfully applied in the synthesis of trans-stilbene oxide and 1,2-diphenylethane. The catalysts were prepared from palladium and/or manganese precursors in the presence of orthosilicates using a sol-gel method and could be reused several times successfully.
Zackaria Nairoukh, David Avnir, and Jochanan Blum. 2013. “Acid-Catalyzed Hydration of Alkynes in Aqueous Microemulsions.” ChemSusChem 2013, 6, 430 – 432. Publisher's Version Abstract
Terminal aromatic alkynes are converted rapidly into ketones in a regioselective manner by treatment of their microemulsions with 0.33?M mineral acid between 80 and 140?°C. Internal and aliphatic acetylenes are likewise hydrated, but require longer reaction periods. The products are easily isolated from the reaction mixtures by phase separation. Replacement of H2O by D2O leads to the formation of trideuteriomethyl ketones.