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Gram-Scale Synthesis of Amines Bearing a gem-Difluorocyclopropane Moiety

organic chemistry, spectroscopy, SYNTHESIS

Nov 102017

Image result for National Taras Shevchenko University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine

Ukraine

Abstract

The synthesis of monocyclic, spirocyclic and fused bicyclic secondary amines bearing a gem-difluorocyclopropane moiety via difluorocyclopropanation of unsaturated N-Boc derivatives using the trifluoromethyl(trimethyl)silane/sodium iodide [CF₃SiMe₃-NaI] system is described. The relative order of the substrate reactivity is established. It is shown that for the reactive alkenes the standard reaction conditions can be used, whereas for the substrates with low reactivity, slow addition of the Ruppert–Prakash reagent is necessary.

Gram-Scale Synthesis of Amines Bearing a gem-Difluorocyclopropane Moiety

Authors., Pavel S. Nosik,

DOI: 10.1002/adsc.201700857

Pavel S. Nosik,a.b Andrii O. Gerasov,a Rodion O. Boiko,a Eduard Rusanov,b Sergey V. Ryabukhin,c Oleksandr O. Grygorenko,c * Dmitriy M. Volochnyukb

a Spectrum Info Ltd., Life Chemicals Inc., Murmanska Street 5, Kyiv 02094, Ukraine

b Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine

c National Taras Shevchenko University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine

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* Corresponding author. E-mail: gregor@univ.kiev.ua.

Oleksandr Grygorenko

Ph D

Professor (Associate)

National Taras Shevchenko Univ… , Kiev · Faculty of Chemistry

National Taras Shevchenko University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine

National Taras Shevchenko University of Kyiv

Department

Faculty of Chemistry

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Dmitriy M. Volochnyuk

Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine

Dmitriy M. Volochnyuk was born in 1980 in Irpen, Kyiv region, Ukraine. He graduated from Kyiv State Taras Shevchenko University in 2002 and was awarded his M.S. degree in chemistry. He received his Ph.D. in organic chemistry in 2005 from the Institute of Organic Chemistry, National Academy of Sciences of Ukraine under the supervision of Dr. A. Kostyuk for research on the chemistry of enamines. At present, he divides his time between the Institute of Organic Chemisty, as Deputy Head of Organophosphorus Department and Senior Researcher, and Enamine Ltd (Kyiv, Ukraine), as Director of Chemistry. His main scientific interests are related to fluoroorganic, organophosphorus, heterocyclic and combinatorial chemistry, and multistep organic synthesis. He is a coauthor of more than 80 papers

Given that the incorporation of small fluorinated fragments in drug-like molecules continues to rise, this has created an onus on the synthetic community to provide robust, scalable routes to these molecules of interest. Grygorenko and co-workers have reported on a synthesis of amines featuring a gem-difluorocyclopropane moiety using the readily available Ruppert–Prakash reagent ( Adv. Synth. Catal. 2017, 10.1002/adsc.201700857).
Evaluating a series of olefins under the standard reaction conditions in refluxing THF indicated that only the most reactive olefins (gem-disubstituted) provided good yields of the desired cyclopropane, while other solvents proved to be ineffective. Conducting a control experiment omitting the substrate demonstrated that the key issue herein was competitive decomposition of the TMSCF₃ to a series of gaseous byproducts under the reaction conditions.
Whereas continuous flow provides a potential to mitigate against this, the current report demonstrated that slow addition of the reagent to the reaction mixture also provided a practical solution to this problem.
Employing this approach enabled not only excellent conversions and yields to be realized but also allowed reactivity trends to be identified. In general, gem-disubstituted are the most reactive with the trend correlating with steric hindrance.
For other classes of olefins, electronics are the major factor with the ability of the substituents to stabilize a positive charge in the transition state consistent with a nonsynchronous formation of the two sigma bonds in the cycloaddition the key consideration. The removal of the Boc-protecting group under standard acidic conditions provided the amines as their hydrochloride salts.
Eduard Rusanov

PhD

Head of Crystallographic Lab./Director of the crystallographic facility Nat. Acad. of Sci. Ukraine ‘Single Mjlecule Crystallography’ at IOC

Institute of Organic Chemistry… · DEPARTMENT OF PHYSICOCHEMICAL INVESTIGATIONS