enamine diazoalkanes 2014
TRANSCRIPT
CF3CHN2, C2F5CHN2:underestimated reagents
for organic synthesis
(Enamine Ltd, Kyiv, Ukraine)
Dr. Pavel Mykhailiuk
Kyiv
www.enamine.net
World's largestproducer of building blocks
Founded in 1991
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100.000 building blocksin stock
It will take 300 years to test the whole collection,
when using 1 building block a day.
Founded in 1991
www.enamine.net 5
“~20% of drugs contain Fluorine”
S. Purser at al. Chem. Soc. Rev. 2008, 320 (rev.)
VinflunineFabre, 1998
CitafloxacineDaiichi, 2008
CarmegliptinRoche, 2010
VinflunineFabre, 1998
www.enamine.net 6
“Industrial production of drugs needspractical reactions”
S. D. Roughley et al. J. Med. Chem. 2011, 3451 (rev.)
www.enamine.net 7H. Gilman, R. G. Jones JACS, 1943, 1458.
For 60 years CF3CHN2 was rarely used in chemistry.
www.enamine.net 8
19F-label for Proline
2008
P. Mykhailiuk et al. ACIE 2008, 5765.
19F
www.enamine.net 9P. Mykhailiuk et al. ACIE 2008, 5765.
www.enamine.net 10
Ar
www.enamine.net 11
Advanced amines fordrug discovery
O. Artamonov et al. EurJOC 2014, 3592.
www.enamine.net 12O. Artamonov et al. EurJOC 2014, 3592.
X-Ray
CuClCF3CHN2
25%NBoc
OH
NBoc
NBoc
F3C H
HNH
F3C H
H
TFA
1. TosCl2. KOtBu
55%
N
F3C
Boc
Pd/C, H2 quant.
HCl
MeOHNH
F3C
quant.
92%
CH2Cl2 CH2Cl2
MeOH
www.enamine.net 13O. Artamonov et al. EurJOC 2014, 3592.
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CF3CHN2 (gas)
CuClEDG
F3C
EDG
EDG: electron-donatinggroup
O. Artamonov et al. EurJOC 2014, 3592.P. Mykhailiuk et al. Synthesis 2008, 1741.P. Mykhailiuk et al. ACIE 2008, 5765.
www.enamine.net 15O. Artamonov et al. EurJOC 2014, 3592.P. Mykhailiuk et al. Synthesis 2008, 1741.P. Mykhailiuk et al. ACIE 2008, 5765.
www.enamine.net 16
Easy to do
No purification
Scalable (1g-5g-10g)
One-pot, RT, no inert atmosphere, no catalysts,common solvents,no gaseous reagents,no side products,100% yield
www.enamine.net 17E. Slobodyanyuk et al. EurJOC 2014, 2487.
www.enamine.net 18E. Slobodyanyuk et al. EurJOC 2014, 2487.
www.enamine.net 19
For unclear reasonsC2F5CHN2 was unknown
www.enamine.net 20P. Mykhailiuk Chem. Eur. J. 2014, 4942.
www.enamine.net 21P. Mykhailiuk Beilstein JOC 2014, in press.
www.enamine.net 22
www.enamine.net 23
“Production of drugs and argochemicalsneeds fluorinated molecules
and practical reactions”
S. D. Roughley et al. J. Med. Chem. 2011, 3451 (rev.) S. Purser at al. Chem. Soc. Rev. 2008, 320 (rev.)
www.enamine.net 24
www.enamine.net 25H. Gilman, R. G. Jones JACS, 1943, 1458.
For 60 years CF3CHN2 was rarely used in chemistry.
However, during the past 5 years, in-situ generated CF3CHN2was used in more than 70 papers:
Prof. G. Simonneaux, Prof. E. Carreira, Prof. J.-A. Ma,Prof. D. Cahard,Prof. W. Xiao,Prof. M. Duncton, Prof. G. Molander,Prof. J. Wang.
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AcknowledgementEvgeniy Slobodyanyuk
Olexyi Artamonov
Prof. Anne UlrichProf. Igor KomarovProf. Olha ZaporozhetsProf. Andrey Tolmachev500 chemists
O. Ishenko, V. Stepanenko
(synthesis of C2F5CH2NH2)
Unique alkynes and alkenes were synthesized by our chemists at Enamine.
www.enamine.net
CF3CHN2, C2F5CHN2:underestimated reagents
for organic synthesis