Gram‐Scale Synthesis of Amines Bearing a <i>gem</i>‐Difluorocyclopropane Moiety

Nosik, Pavel S.; Gerasov, Andriy O.; Boiko, Rodion O.; Русанов, Эдуард Б.; Grygorenko, Oleksandr O.; Volochnyuk, Dmitriy M.

doi:10.1002/adsc.201700857

Cited by 37 publications

(33 citation statements)

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“…[232] Recent years have witnessedt he publication of numerouss ynthetic works on novel advanced buildingb locks for drug discovery,f ocusingm ainly on unusual bicyclic, spirocyclic, heteroaliphatic,o rh eteroaromatic compounds, especially those with fluorine atoms; selected examples are given in Figure 44. [233][234][235][236][237][238][239][240]…”

Section: Building Blocks For Drug Discoverymentioning

confidence: 99%

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

Grygorenko

Volochnyuk

Ryabukhin

et al. 2019

Chemistry A European J

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All pharmaceutical products contain organic molecules; the source may be a natural product or a fully synthetic molecule, or a combination of both. Thus, it follows that organic chemistry underpins both existing and upcoming pharmaceutical products. The reverse relationship has also affected organic synthesis, changing its landscape towards increasingly complex targets. This Review article sets out to give a concise appraisal of this symbiotic relationship between organic chemistry and drug discovery, along with a discussion of the design concepts and highlighting key milestones along the journey. In particular, criteria for a high‐quality compound library design enabling efficient virtual navigation of chemical space, as well as rise and fall of concepts for its synthetic exploration (such as combinatorial chemistry; diversity‐, biology‐, lead‐, or fragment‐oriented syntheses; and DNA‐encoded libraries) are critically surveyed.

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Section: Building Blocks For Drug Discoverymentioning

confidence: 99%

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

Grygorenko

Volochnyuk

Ryabukhin

et al. 2019

Chemistry A European J

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136

123

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“…Because application of these reaction conditions to functionalized substrates is limited by their thermal stability and their susceptibility to side reactions at elevated temperatures, a selection of a TMSCF 3 –NaI system as a difluorocarbene equivalent was envisaged. The usage of TMSCF 3 , which is also referred as Ruppert–Prakash reagent, for gem ‐difluoromethylation reaction was first developed by Hu, Prakash and co‐workers, and was further adapted for preparation of gem ‐difluorocyclopropanes bearing diverse functional groups . Nonetheless, the addition of difluorocarbene equivalent derived from TMSCF 3 to alkenylboronic derivatives was unknown until the present study.…”

Section: Introductionmentioning

confidence: 96%

gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF₃SiMe₃–NaI System

et al. 2020

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Difluorocyclopropanation of alkenyl trifluoroborates using TMSCF 3 -NaI system was reported for the first time. The developed method allowed preparation of monocyclic, spiroand fused-bicyclic gem-difluorocyclopropanes bearing addi-groups. [20][21][22][23][24] Nonetheless, the addition of difluorocarbene equivalent derived from TMSCF 3 to alkenylboronic derivatives was unknown until the present study. Scheme 1. Difluorocyclopropanation of alkenylboronic derivatives.In this work, application of TMSCF 3 -NaI system in refluxing THF (66°C) for the synthesis of gem-difluorocyclopropyl boronic derivatives and its effectiveness for multigram scale synthesis is reported (Scheme 1). It is shown that alkenyl trifluoroborates are optimal substrates for the preparation of aliphatic derivatives which facilitate isolation of the target products. The studied reaction scope included substrates bearing secondary N-Boc protected amine, ester, ether, phenyl and cyclopropyl moieties and provided products with spiro-and fused-bicyclic molecular topologies. Results and DiscussionOur study commenced with testing TMSCF 3 -NaI system in reaction with substrate 5a (Scheme 2), for which the difluorocyclopropanation using XCF 2 CO 2 Na (X = Cl, Br) at 180°C and 150°C, Scheme 2. Attempted difluorocyclopropanation of alkenyl boronic derivatives using the TMSCF 3 -NaI system. 2218Scheme 3. Preparation of trifluoroborate salts 7 from pinacolboronates 9.Scheme 4. Synthesis of pinacolboronates 9e (A) and 9p (B).

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“…While a number of papers describe synthetic approaches to the compounds having a gem ‐difluorocyclopropyl group attached to the carbon atom, as well as their chemical transformations,, the corresponding N ‐substituted analogues are much less studied. Most of them referred to the parent gem ‐difluorocyclopropylamine ( 5 ) or its derivatives (Scheme );, it should be noted that similar aliphatic amines (e.g.…”

Section: Introductionmentioning

confidence: 99%

“…In a recent paper by Xiao and co‐workers, a few N ‐difluorocyclopropyl‐substituted indole, benzimidazole and benzotriazole derivatives of general formula 7 were synthesized by N ‐alkylation of the corresponding heterocyclic anions with tosylate 8 . In the current work we describe an alternative approach to N ‐difluorocyclopropyl‐substituted azoles, which is based on the difluorocyclopropanation of the corresponding N ‐vinylazoles 9 with the CF 3 SiMe 3 –NaI system, which was initially developed by Hu, Prakash, Olah and co‐workers in 2011, and has been used by many other groups since then . Although this method appeared to be suitable only for the pyrazole derivatives, a wide range of functionalized compounds could be obtained, which are valuable low‐molecular‐weight building blocks for drug discovery and agrochemistry.…”

Section: Introductionmentioning

confidence: 99%

N‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity

et al. 2019

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Difluorocyclopropanation of N‐vinylazoles with the CF3SiMe3–NaI system was studied. It was found that N‐vinylpyrazoles could be transformed into the corresponding N‐difluorocyclopropyl‐substituted derivatives. The method was efficient on a 100 g scale and could be applied for the preparation of various functionalized regioisomeric pyrazole derivatives bearing a gem‐difluorocyclopropane moiety, such as amines, carboxylic acids, aldehydes, bromides, and boronic esters. It was found that N‐difluorocyclopropylpyrazole moiety tolerated many common reagents including nitrating mixture, bromine, aqueous acids and alkali, KMnO4, LiBH4, and Pd0 complexes; it was unstable towards AlCl3, catalytic hydrogenation and lithiation conditions. The products obtained are advanced building blocks which of potential importance to medicinal and agrochemistry.

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

Cited by 37 publications

References 50 publications

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF₃SiMe₃–NaI System

N‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity

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

Cited by 37 publications

References 50 publications

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF3SiMe3–NaI System

N‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity

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gem‐Difluorocyclopropanation of Alkenyl Trifluoroborates with the CF₃SiMe₃–NaI System