new frontiers of difluorocyclopropanation of … · • 2.7m screening compounds, the world’s...
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NEW FRONTIERS OF DIFLUOROCYCLOPROPANATION OF ALKENES USING RUPPERT–PRAKASH REAGENT
Prof. Sergey V. Ryabukhin Prof. Dmitriy M. Volochnyuk
257th ACS National Meeting April 2019 Orlando
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Enamine profile • Scientifically driven chemical company • Privately owned, founded in 1991 • Research & Production facility in Kiev, Ukraine • Over 500 synthetic chemists • 2.7M Screening Compounds, the world’s largest! • 180k Building Blocks, 50% of the world’s stock! • Biology services: ADME/T tests, animal studies and molecular screening • No own drug research, 100% service orientated • Representative and distribution offices in EU, USA, Japan, and China
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Goldberg F. W. et al Drug Discov Today 2015, 20, 11-17. Itoh, T. 2009, in Fluorine in Medicinal Chemistry & Chemical Biology
Why are difluorocyclopropanes?
Chapter 9: gem-Difluorocyclopropanes as Key
Building Blocks for Novel Biologically Active Molecules
All Hallmarks of the Building Blocks for MedChem:
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Why is Difluorocyclopropanation?
J. Am. Chem. Soc., 1996, 118, 8860 – 8870 .
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Starting materials
! Tolerant to majority of protected common functional group
Prakash Protocol: 2,5 eq TMSCF3, 0,2 eq NaI, 650C, 2 h.
Prakash G. K. S. et al Angew. Chem. Int. Ed. 2011, 50, 7153. Bychek R., Levterov V. et al Eur. J. Org. Chem, 2018, 24, 12291.
Products Dr. P. Mykhailiuk
Tolerance of FG to Prakash protocol
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TMSCF3/NaI Prakash protocol: limitation Failed but not critical Failed but CRITICAL!!!
not applicable for wide using
+ in some cases Dolbier (FSO2CF2SiMe3) or Haszeldine
(ClF2CO2Na or BrF2CO2Na) reagents are applicable
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TMSCF3/NaI competition experiment
Solvent Conversion of 9a, (%)
after 2 h after 4 h
THF >99 >99
1,4-Dioxane 0 N/A
t-BuOMe 0 N/A
MeCN 0 N/A
1,2-DME 33 77
Adv. Synth. Catal., 2017, 359, 3126.
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TMSCF3/NaI blank experiment
Batch Prakash protocol to Flow Charette protocol (10 min residence time) leads to increasing of the yield.
Angew. Chemie Int. Ed. 2011, 50, 7153–7157 Org. Lett., 2016, 18, pp 1988–1991
Modified batch protocol (“slow addition”): Slow (up to 24h) addition of the excess Me3SiCF3 (up to 10 eq) to the reaction mixture according to the difluorocyclopropanation kinetics.
Adv. Synth. Catal., 2017, 359, 3126.
Pavel Nosik
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TMSCF3/NaI “slow addition”
Prakash protocol: Slow addition protocol:
Adv. Synth. Catal., 2017, 359, 3126.
trace amounts of desired product
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TMSCF3/NaI “slow addition” impact Chemical space of BB covered by TMSCF3
difluorocyclopropanation as a key step (Enamine LTD data)
New fluorinated BBs with diverse 3D architecture
Procedure # of BBs synthesi
sed
# of BBs included
into validated virtual set
Prakash 76 1043
Prakash + “slow addition” 121 1812
Another reagents 112 2486
Adv. Synth. Catal., 2017, 359, 3126.
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TMSCF3/NaI “slow addition” impact
M. Goswami et al Chem. Commun., 2017, 53, 4382-4385
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TMSCF3/NaI “slow addition” impact
Adv. Synth. Catal. 2018, 360, 4104–4114
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TMSCF3/NaI “slow addition”
Adv. Synth. Catal. 2018, 360, 4104–4114
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TMSCF3/NaI “slow addition”
First functionalized alkenes:
2017 2018
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TMSCF3/NaI “slow addition” impact
Nosik, P. S. et al, Gram‐Scale Synthesis of Amines Bearing a
gem‐Difluorocyclopropane Moiety Adv. Synth. Catal. 2017, 359, 3126
Very Important Publication Nosik, P. S., et al Transition Metal‐free
gem‐difluorocyclopropanation of Alkenes with CF3SiMe3−NaI System: a Recipe for
Electron‐deficient Substrates. Adv. Synth. Catal. 2018, 360, 4104–4114
How to train the dragon?
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Difluorocyclopropanes
https://www.enamine.net/download/posters/Enamine_Difluorocyclopropanes-for-drug-discovery_A4_2018.pdf
Adv. Synth. Catal. 2018, 360, 4104–4114
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1-hetaryl-2,2-difluorocyclopropanes
In a case of two fluorine atoms only cyclopropane derivatives “in a Ro2” e.g. ΔMW of BB fragment <
200 Da
Drug Discov Today 2015, 20, 11-7
Heterocycle: decreased LogP and increased water solubility in comparison with arene derivative
Eur J Med Chem. 2016, 29, 1057-1068.
J. Fluor. Chem. 2019, 217, 80–89.
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Pyrazole: good model heterocycle
• 3- p-acceptor • 4- p-donor • 5- p-amphoteric
Monatsh. Chem. 2016, 147, 1629-1634.
SynOpen 2017, 01, 84-90.
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1-pyrazolyl-2,2-difluorocyclopropanes
General retrosynthetic scheme
Experimental validation: “push-pull like” alkene still does not working but “kapto-dative like” alkenes are active in a “slow
addition” protocol conditions
J. Fluor. Chem. 2019, 217, 80–89.
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Limitations: Expected
K. R. Gassen, et al J. Fluor. Chem. 1990, 49, 127–139 V. Kubyshkin, et al J. Fluor. Chem. 2015, 175, 73–83.
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Limitations: Unexpected
Schneider, T. F. et al Angew. Chem. Int. Ed. 2014, 53, 2–22
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# FG Heterocycle type
BB type BB Type
1 COOH, p-acceptor feasible
feasible but problematic
2 - //- p-amphoteric/neutral feasible with low yield 3 - //- p-donor non- feasible
4 CH2OH, CH2NH2
p-acceptor feasible
feasible but problematic
5 - //- p-amphoteric/neutral feasible with low yield 6 - //- p-donor
7 NH2 p-acceptor non- feasible non- feasible 8 - //- p-amphoteric/neutral
9 - //- p-donor
General guidelines
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Future directions
Tolerate Unstable towards
HNO3 – H2SO4
Br2
DMF – POCl3
LiBH4
KMnO4 or MnO2
2/12 M aq. HCl, 100 C
2 M aq. NaOH, 100 C
Pd(dppf)Cl2, B2Pin2, 80 Ca
Pd(PPh3)4, 85 C
Pd(OAc)2, PPh3, CuI, 85 C
n-BuLi, LiHMDS, LDA or
i-PrMgClLiCl, THF, –78 C
LiTMP, THF, –100C
H2 (1 atm), Pd-C, rt
CH3C(O)Cl, AlCl3
Tolerance of N-(gem-difluorocyclopropyl)pyrazoles to common organic reactions
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Summary
Scope of the substrates Extremely expanded
Understanding of scope No
Mechanistic investigations No
Scale up To 300 g Tolerance to common FG or its
protected forms Investigated
Tolerance to deprotection of final functional F2cPr Investigated
Tolerance to common organic reactions of final functional
F2cPr Partially investigated
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Acknowledgements
Pavel S. Nosik Dr. Oleksandr O. Grygorenko Kostiantyn P. Melnykov Andrii S.Poturai Mykola O. Pashko
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THANK YOU FOR YOUR KIND ATTENTION