Reactivity Parameters for Enamine Activated Reactions - Ludwig
Enamine fluorinated heterocycles 2015
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Fluorinated heterocycles for agrochemistry from novel 19F-diazoalkanes
Pavel Mykhailiuk, PhD
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I do love Metz already!
but…
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Metz
Kyiv 3 hours
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This is Kiev:
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World's largest producer of building blocks
~120.000 building blocks (stock, gram-scale)
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~120.000 compounds on stock (gram-scale)
~60.000 building blocks
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~120.000 building blocks
~120.000 citizens
1 building block / 1 citizen
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500 chemists 10 own buildings
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50 papers
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Synthesis of
agrochemistry-related heterocycles from novel 19F-diazoalkanes
Pavel Mykhailiuk, PhD
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CF3
N2
H. Gilman, R. G. Jones JACS, 1943, 1458.
Until 2006 CF3CHN2 was rarely used in chemistry.
EtO2C
N2
Ethyl diazoacetate is extremely popular (> 100 reactions).
T. Curtius Chem. Ber. 1883, 2230.
Liquid
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Kyiv
Enamine Ltd: synthesis of 19F-amino acids
Karlsruhe
Anne Ulrich: study of peptides by ss 19F-NMR
2008
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19F-label for Proline
2008
P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2008, 5765.
19F
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www.enamine.net 14 P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2008, 5765.
Synthesis of 19F-label for Proline
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Ar
F3C
NH2
*HCl
NaNO2
dry CuCl87%
N CO2Me
Boc
CF3N CO2Me
BocAr
MgSO4
CF3
N2
individual dry gas
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NH
CF3
NH
CF3
NH
CF3
Advanced CF3-amines for drug discovery
O. Artamonov et al. EurJOC 2014, 3592.
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www.enamine.net 17 O. Artamonov et al. EurJOC 2014, 3592.
Olexyi Artamonov
Synthesis of CF3-amines
CuClCF3CHN2
25%NBoc
OH
NBoc
NBoc
F3C H
HNH
F3C H
H
TFA
1. TosCl2. KOtBu
55%quant.
CH2Cl2 CH2Cl2
F3C
H
H NH
F3C
H
H NH
NH
F3C
NH
F3CH
H
H
H
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CF3-cyclopropanation of alkenes
N
F3C
NF3C
N
F3C
Boc Boc
Boc
F3C F3C
O OF3C
61%
71%
24%51%48%
69%
N
F3C
Boc
83%
CO2Me
F3C
11%
O. Artamonov et al. EurJOC 2014, 3592.
P. Mykhailiuk et al. Synthesis 2008, 1741.
P. Mykhailiuk et al. ACIE 2008, 5765.
CF3
NH2
*HCl 1) NaNO2, rt
EDG: electron-donation group
CF3
N2
individual dry gas
CH2Cl2/H2O EDG
2) Ar / MgSO4 dry CuCl
CF3
EDG
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Do we need dry CF3CHN2 here?
Do we need to isolate it then?
CF3-cyclopropanation of alkenes
HNN CO2Me
CF3
CO2Me[3+2]
CF3
NH2
*HCl 1) NaNO2, rt
EDG: electron-donation group
CF3
N2
individual dry gas
CH2Cl2/H2O EDG
2) Ar / MgSO4 dry CuCl
CF3
EDG
[3+2]-cycloaddition with alkenes
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Easiest reaction in organic chemistry
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
HNN CO2Me
CF3CF3
NH2
*HCl NaNO2
one-pot
CF3
N2
in situ-generated
CH2Cl2/H2ORT
CO2Me
[3+2]
97%
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HNN EWG
CF3
CF3
NH2
*HCl NaNO2
one-potEWG: electron-withdrawing group
CF3
N2
in situ-generated
CH2Cl2/H2ORT
EWG
[3+2]
E. Slobodyanyuk et al. EurJOC 2014, 2487.
Evgeniy Slobodyanyuk
HNN
F3C
CN
HNN
F3C
CO2Me
HNN
F3C
SO
OHN
N
F3C
S PhO
O
HNN
F3C
O
HNN
F3C
O
NN
NF3C
O
O
Ph
HNN
F3C
S FO
O
NN
F3C
N
O
O
HNN
F3C
CO2tBu
HNN
F3C
CO2Me
CO2Me
HNN
F3C
CO2Et
CO2Et
NN
F3C
CO2Me
NN
F3C
CO2Me
CO2Me
97% 98%95%92%
80% 97%96%
94%
75%
98%94%97%
75%
98%
CF3-pyrazolines
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NN
F3C
SO2NH2
NN
F3C
F
SO2NH2
MavacoxibCelecoxib
NN
F3C
Penthiopyrad
ONH
S
NN
F3C
Razaxaban
HN
O N
N
F
NN OH2N
NN
F3CHN
O SO2
AS-136A
N
Bioactive CF3-pyrazoles
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www.enamine.net 23 E. Slobodyanyuk et al. EurJOC 2014, 2487.
NNH
F3C
CO2Me
NNH
F3C
NNH
F3C
NNH
F3C
NNH
F3C
NNH
F3CHN
O
NNH
CF3
P PhO
NNH
F3C
NNH
F3C
CO2Me
CO2Me
NNH
F3C
CO2Et
CO2Et
97% 98%95%92%
80% 97%96%94%
75% 94%97%
Ph
O
Ph
O
Ph
O S
N
N
N
NNH
F3C
CF3
CF3
NNH
F3C
96%
S
N
NNH
EWG
CF3
CF3
NH2
*HCl NaNO2
one-potEWG: electron-withdrawing group
CF3
N2
in situ-generated
CH2Cl2/H2ORT
[3+2]
EWG
CF3-pyrazoles
Evgeniy Slobodyanyuk
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C2F5
N2
2014: unknown
O
AcOH
C2F5
Lonaprisan
(Bayer HC; Phase II)
H
HH
HHO
H
OH
9S
OC2F5
3
Fulvestrant
(AstraZeneca; launched)
O
C2F5
KC-515
(Chugai; preclinical)
HN ONC
2
F
F
anticancer
anticancer
antimigraine
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NNH
C2F5
CO2Me
NNH
C2F5
NNH
C2F5
NNH
C2F5
NNH
C2F5
NNH
C2F5HN
O
NNH
C2F5
P PhO
NNH
C2F5
NNH
C2F5
97% 98%95%92%
80% 97%96%94%
41% 94%62%
Ph
O
Ph
O
Ph
O S
N
N
N
NNH
C2F5
CF3
CF3
NNH
C2F5
96%
S
N
O
SiNNH
C2F5
O
Si
Cl
P. Mykhailiuk Chem. Eur. J. 2014, 4942; P. Mykhailiuk Beilstein J. Org. Chem. 2015, 16; P. Mykhailiuk Org. Biomol. Chem. 2015, 3438.
NNH
EWG
C2F5C2F5
NH2
*HCl NaNO2
one-pot
C2F5
N2
in situ-generated
CH2Cl2/H2ORT
[3+2]
EWG
C2F5-pyrazoles
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N2
F
F 2015: unknown
BixafenBayer CS
IsopyrazamSyngenta
NN
FF
ONH
F
Cl
Cl
NN
FF
ONH
NN
FF
ONH
F
FF
NN
FF
ONH
SedaxaneSyngenta
FluxapyroxadBASF
BenzovindiflupyrSyngenta
NN
FF
ONH
ClCl
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In-situ generation of CHF2CHN2
*HCl
NH2 N2
O
F
FNaNO2
CH2Cl2/H2ORT
NH2
F
F N2
F
FCHCl3
in situ-generated
HOAc (cat.)
reflux
CO2Me
NNH
FF
CO2Me
76%
tBuONO
one-pot[3+2]
non-aqueous conditions?
P. Mykhailiuk Angew. Chem. Int. Ed. 2015, 6558.
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NNH
CO2Me
76%
41%
NNH
31%
S
N
FF
NNH
CO2Et
81%
FF
NNH
CO2iPr
73%
FF
NNH
61%
FF
O
NNH61%
FF
O
Ph NNH
71%
FF
O
PhN
NH
65%
FF
O
NNH
51%
FF
O
HN
FF
NNH
PO
FF
PhPh N
NH
CO2Me
76%
FF
CO2Me
NNH
FF
O Cl
49%
CHF2-pyrazoles
NH2
F
F N2
F
FCHCl3
in situ-generated
HOAc (cat.)
reflux
EWG
NNH
FF
EWG
tBuONO
one-pot[3+2]
Finally, my photo!
P. Mykhailiuk Angew. Chem. Int. Ed. 2015, 6558.
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Some unpublished data
colleagues from Syngenta, it is not interesting
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NC
N2
2015: not used
NN NH2
CF3
Fipronilinsecticide
BASF
S(O)CF3
Cl Cl
NN NH2
CF3
Ethiproleinsecticide
BASF
S(O)Et
Cl Cl
NN N
H
CF3
Pyrafluproleinsecticide
BASF
SCH2F
Cl Cl
NNN
Pyrazlonilherbicide
Hoechst Schering
NN Cl
NC
NC
NC
NC
Pz
T. Curtius Chem. Ber. 1898, 2490.
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www.enamine.net 33 Unpublished results
CN-pyrazoles
NNH
EWG
NCNC
NH2
*HCl NaNO2
one-pot
NC
N2
in situ-generated
CHCl3/H2O
reflux[3+2]
EWG
RT
NNH
NC
CO2Me
76%
NNH
NC
CO2Et
81%
NNH
NC
CO2iPr
73%
NNH
NC
61%O
NNH
NC
61%O
Ph NNH
NC
71%
O
PhN
NH
NC
65%
O
NNH
NC
51%
O
HN
NNH
NC
CO2Me
76%
CO2Me
NNH
NC
O F
49%
Br
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World's largest producer of building blocks
~120.000 building blocks (stock, gram-scale)
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50 papers
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CF3
N2
EtO2C
N2
popular (> 1000 reactions)
2014:
in situ-generated RCHN2
>70 papers
N2
F
F
NC
N2
C2F5
N2
2015: unpublished
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Acknowledgement
Evgeniy Slobodyanyuk
Olexyi Artamonov
Anton Arkhipov
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Thank you!
Enamine: world's largest supplier of building blocks 2015