enamine fluorinated heterocycles 2015
TRANSCRIPT
Fluorinated heterocycles for agrochemistry from novel 19F-diazoalkanes
Pavel Mykhailiuk, PhD
www.enamine.net 2
I do love Metz already!
but…
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
Synthesis of
agrochemistry-related heterocycles from novel 19F-diazoalkanes
Pavel Mykhailiuk, PhD
www.enamine.net 11
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
Kyiv
Enamine Ltd: synthesis of 19F-amino acids
Karlsruhe
Anne Ulrich: study of peptides by ss 19F-NMR
2008
www.enamine.net 13
19F-label for Proline
2008
P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2008, 5765.
19F
www.enamine.net 14 P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2008, 5765.
Synthesis of 19F-label for Proline
www.enamine.net 15
Ar
F3C
NH2
*HCl
NaNO2
dry CuCl87%
N CO2Me
Boc
CF3N CO2Me
BocAr
MgSO4
CF3
N2
individual dry gas
www.enamine.net 16
NH
CF3
NH
CF3
NH
CF3
Advanced CF3-amines for drug discovery
O. Artamonov et al. EurJOC 2014, 3592.
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
www.enamine.net 18
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
www.enamine.net 22
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
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
www.enamine.net 24
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
www.enamine.net 25
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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www.enamine.net 27
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.
www.enamine.net 29
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.
www.enamine.net 30
www.enamine.net 31
Some unpublished data
colleagues from Syngenta, it is not interesting
www.enamine.net 32
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.
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)
www.enamine.net
50 papers
www.enamine.net 36
CF3
N2
EtO2C
N2
popular (> 1000 reactions)
2014:
in situ-generated RCHN2
>70 papers
N2
F
F
NC
N2
C2F5
N2
2015: unpublished
www.enamine.net 37
Acknowledgement
Evgeniy Slobodyanyuk
Olexyi Artamonov
Anton Arkhipov
Thank you!
Enamine: world's largest supplier of building blocks 2015