The use of fluorinated chemical building blocks for medicinal chemistry and drug discovery applications.

1. CF3CHN2, C2F5CHN2:
underestimated reagents
for organic synthesis
(Enamine Ltd, Kyiv, Ukraine)
Dr. Pavel Mykhailiuk

2. Kyiv

3. www.enamine.net
World's largest
producer of building blocks
Founded in 1991

4. www.enamine.net
100.000 building blocks
in stock
It will take 300 years
to test the whole collection,
when using 1 building block a day.
Founded in 1991

5. www.enamine.net 5
“~20% of drugs contain Fluorine”
S. Purser at al. Chem. Soc. Rev. 2008, 320 (rev.)
Vinflunine
Fabre, 1998
Citafloxacine
Daiichi, 2008
Carmegliptin
Roche, 2010
Vinflunine
Fabre, 1998

6. www.enamine.net 6
“Industrial production of drugs needs
practical reactions”
S. D. Roughley et al. J. Med. Chem. 2011, 3451 (rev.)

7. www.enamine.net 7
H. Gilman, R. G. Jones JACS, 1943, 1458.
For 60 years CF3CHN2 was rarely used in chemistry.

8. www.enamine.net 8
19F-label for Proline
2008
P. Mykhailiuk et al. ACIE 2008, 5765.
19F

9. www.enamine.net 9P. Mykhailiuk et al. ACIE 2008, 5765.

10. www.enamine.net 10
Ar

11. www.enamine.net 11
Advanced amines for
drug discovery
O. Artamonov et al. EurJOC 2014, 3592.

12. www.enamine.net 12O. Artamonov et al. EurJOC 2014, 3592.
X-Ray
CuCl
CF3CHN2
25%
N
Boc
OH
N
Boc
N
Boc
F3C H
H
N
H
F3C H
H
TFA
1. TosCl
2. KOtBu
55%
N
F3C
Boc
Pd/C, H2
quant.
HCl
MeOH
N
H
F3C
quant.
92%
CH2Cl2 CH2Cl2
MeOH

13. www.enamine.net 13O. Artamonov et al. EurJOC 2014, 3592.

14. www.enamine.net 14
CF3CHN2 (gas)
CuCl
EDG
F3C
EDG
EDG: electron-donating
group
O. Artamonov et al. EurJOC 2014, 3592.
P. Mykhailiuk et al. Synthesis 2008, 1741.
P. Mykhailiuk et al. ACIE 2008, 5765.

15. www.enamine.net 15
O. Artamonov et al. EurJOC 2014, 3592.
P. Mykhailiuk et al. Synthesis 2008, 1741.
P. Mykhailiuk et al. ACIE 2008, 5765.

16. 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

17. www.enamine.net 17E. Slobodyanyuk et al. EurJOC 2014, 2487.

18. www.enamine.net 18E. Slobodyanyuk et al. EurJOC 2014, 2487.

19. www.enamine.net 19
For unclear reasons
C2F5CHN2 was unknown

20. www.enamine.net 20P. Mykhailiuk Chem. Eur. J. 2014, 4942.

21. www.enamine.net 21P. Mykhailiuk Beilstein JOC 2014, in press.

22. www.enamine.net 22

23. www.enamine.net 23
“Production of drugs and argochemicals
needs 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.)

24. www.enamine.net 24

25. www.enamine.net 25
H. 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 CF3CHN2
was 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.

26. www.enamine.net
Acknowledgement
Evgeniy Slobodyanyuk
Olexyi Artamonov
Prof. Anne Ulrich
Prof. Igor Komarov
Prof. Olha Zaporozhets
Prof. Andrey Tolmachev
500 chemists
O. Ishenko,
V. Stepanenko
(synthesis of C2F5CH2NH2)
Unique alkynes and alkenes were
synthesized by our chemists at Enamine.

27. www.enamine.net
CF3CHN2, C2F5CHN2:
underestimated reagents
for organic synthesis