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Fluorinated diazoalkanes:synthesis and application

Pavel Mykhailiuk2016

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World's largestproducer of building blocks

~100.000 compounds on stock(gram-scale)

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500 chemists 10 own buildings private company

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50 papers

www.enamine.net 5H. Gilman, R. G. Jones JACS, 1943, 1458.

Until 2006 CF3CHN2was rarely used in chemistry.

Ethyl diazoacetate is extremely popular (> 100 reactions).

T. Curtius Chem. Ber. 1883, 2230.

Liquid

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19F-label for Proline

2008

P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2008, 5765.

19F

www.enamine.net 7P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2008, 5765.

Synthesis of 19F-label for Proline

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Ar

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Advanced CF3-amines fordrug discovery

O. Artamonov et al. EurJOC 2014, 3592.

www.enamine.net 10O. Artamonov et al. EurJOC 2014, 3592.

Synthesis of CF3-amines

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CF3-cyclopropanation of alkenes

O. Artamonov et al. EurJOC 2014, 3592.P. Mykhailiuk et al. Synthesis 2008, 1741.P. Mykhailiuk et al. ACIE 2008, 5765.

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Do we need dry CF3CHN2 here?

Do we need to isolate it then?

CF3-cyclopropanation of alkenes

[3+2]-cycloaddition with alkenes

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No purification

Scalable (500 g)

one-pot, RT, no inert atmosphere, no catalysts,common solvents,no gaseous reagents,no side products,97% yield

[3+2]-cycloaddition with alkenes

E. Slobodyanyuk et al. EurJOC 2014, 2487.

www.enamine.net 14E. Slobodyanyuk et al. EurJOC 2014, 2487.

CF3-pyrazolines

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Bioaktive CF3-pyrazoles

www.enamine.net 16E. Slobodyanyuk et al. EurJOC 2014, 2487.

CF3-pyrazoles

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CF3

NH2

*HCl NaNO2CF3

N2

in situ-generated

CH2Cl2/H2ORT RT

EWG EWG

Base

EWG EWG

NHN

CF3

Japp-Klingemann reaction

17Unpublished results

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2014: unknown

www.enamine.net 19P. Mykhailiuk Chem. Eur. J. 2014, 4942.P. Mykhailiuk Beilstein J. Org. Chem. 2015, 16.

C2F5-pyrazolines

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C2F4H-pyrazoles

Unpublished results

www.enamine.net 21P. Mykhailiuk Chem. Eur. J. 2014, 4942; P. Mykhailiuk Beilstein J. Org. Chem. 2015, 16; P. Mykhailiuk Org. Biomol. Chem. 2015, 3438.

C2F5-pyrazoles

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2015: not usedproperly

T. Curtius Chem. Ber. 1898, 2490.

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CN-pyrazoles

P. Mykhailiuk EurJOC 2015, 7235.

www.enamine.net 25

www.enamine.net 26

P. Mykhailiuk Chem. Eur. J. 2014, 4942. P. Mykhailiuk Beilstein J. Org. Chem. 2015, 16. P. Mykhailiuk Org. Biomol. Chem. 2015, 3438.P. Mykhailiuk EurJOC 2015, 7235.P. Mykhailiuk Angew. Chem. Int. Ed. 2015, 6558.

Scope

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2015: unknown

www.enamine.net 28

In-situ generation of CHF2CHN2

non-aqueous conditions?

P. Mykhailiuk Angew. Chem. Int. Ed. 2015, 6558.

www.enamine.net 29

CHF2-pyrazoles

P. Mykhailiuk Angew. Chem. Int. Ed. 2015, 6558.

www.enamine.net 30

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popular (> 4000 reactions)

2014:

in situ-generated RCHN2

>70 papers

2015: 2015:

2014:

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500 chemists

Alekseenko A.

Artamonov O.

Artemenko A.

Andrushko O.

Arkhipov A.

Arkhipov V.

Bilenko V.

Chalyk B.

Datcenko O.

Denisenko O.

Dmitriv U.

Druzhenko T.

Granat D.

Gorulia O.

Garbuz P.

Gavrilenko K.

Martirosov R.

Moroz U.

Mituk A.

Mikhalchuk V.

Gryshuk S.

Iminov R.

Komarov I.

Kokhan S.

Kondratov V.

Kubyshkin V.

Khutorianskii A.

Levchenko K.

Logvinenko V.

Ostapchuk E.

Pasternak A.

Parhomenko L.

Pervak I.

Pustovit U.

Radchenko D.

Savich V.

Scherbatiuk A.

Shyshlik O.

Slobodianuk E.

Tkachenko A.

Tkachuk G.

Tolmacheva N.

Tolmachev A.

Trofimchuk S.

Tverdokhlebov A.

Tymtsunik A.

Volochnyuk D.

Yakovenko N.

Yarmolchuk V.

Yarmoluk D.

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